U.S. patent application number 10/627357 was filed with the patent office on 2004-07-15 for amyloid immunization and cox-2 inhibitors for the treatment of alzheimer's disease.
This patent application is currently assigned to Pharmacia Corporation. Invention is credited to Krafft, Grant A., Robertson, David W..
Application Number | 20040138296 10/627357 |
Document ID | / |
Family ID | 31721971 |
Filed Date | 2004-07-15 |
United States Patent
Application |
20040138296 |
Kind Code |
A1 |
Robertson, David W. ; et
al. |
July 15, 2004 |
Amyloid immunization and Cox-2 inhibitors for the treatment of
alzheimer's disease
Abstract
The present invention provides compositions and methods for the
treatment or prevention of Alzheimer's disease. More particularly,
the invention provides a combination therapy for the treatment or
prevention of Alzheimer's disease, wherein the therapy comprises
administering to a subject an amyloid beta vaccine in combination
with a cyclooxygenase-2 selective inhibitor.
Inventors: |
Robertson, David W.;
(Glenview, IL) ; Krafft, Grant A.; (Glenview,
IL) |
Correspondence
Address: |
PHARMACIA CORPORATION
GLOBAL PATENT DEPARTMENT
POST OFFICE BOX 1027
ST. LOUIS
MO
63006
US
|
Assignee: |
Pharmacia Corporation
|
Family ID: |
31721971 |
Appl. No.: |
10/627357 |
Filed: |
July 25, 2003 |
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60402760 |
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60402778 |
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60402674 |
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Current U.S.
Class: |
514/461 ;
514/314; 514/467; 514/568 |
Current CPC
Class: |
A61K 39/0007 20130101;
A61K 31/415 20130101; A61K 31/19 20130101; A61K 31/415 20130101;
A61K 31/4709 20130101; A61K 31/473 20130101; A61P 25/28 20180101;
A61K 31/196 20130101; A61K 31/18 20130101; A61K 31/341 20130101;
A61K 31/473 20130101; A61K 31/382 20130101; A61P 43/00 20180101;
A61K 31/341 20130101; A61K 38/1709 20130101; A61K 31/416 20130101;
A61K 31/18 20130101; A61K 31/42 20130101; A61K 31/382 20130101;
A61K 31/196 20130101; A61K 31/352 20130101; A61K 38/1709 20130101;
A61K 39/0007 20130101; A61K 31/416 20130101; A61K 31/352 20130101;
A61K 31/42 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/461 ;
514/467; 514/314; 514/568 |
International
Class: |
A61K 031/4709; A61K
031/19 |
Claims
What is claimed is:
1. A method for the treatment or prevention of Alzheimer's disease
in a subject, the method comprising administering to the subject a
cyclooxygenase-2 selective inhibitor or a pharmaceutically
acceptable salt or prodrug thereof and an amyloid beta vaccine.
2. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises a chromene compound.
3. The method of claim 2 wherein the chromene compound is a
benzopyran or substituted benzopyran analog.
4. The method of claim 3 wherein the benzopyran or substituted
benzopyran analog is selected from the group consisting of
benzothiopyrans, dihydroquinolines and dihydronaphthalenes.
5. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises a tricyclic compound.
6. The method of claim 5 wherein the tricyclic compound comprises a
benzenesulfonamide or methylsulfonylbenzene.
7. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises a phenyl acetic acid derivative.
8. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises: 232or pharmaceutically acceptable salt or
prodrug thereof.
9. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises: 233or a pharmaceutically acceptable salt or
prodrug thereof.
10. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises a compound of the formula: 234wherein n is an
integer which is 0, 1, 2, 3 or 4; wherein G is O, S or NR.sup.a;
wherein R.sup.a is alkyl; wherein R.sup.1 is selected from the
group consisting of H and aryl; wherein R.sup.2 is selected from
the group consisting of carboxyl, aminocarbonyl,
alkylsulfonylaminocarbonyl and alkoxycarbonyl; wherein R.sup.3 is
selected from the group consisting of haloalkyl, alkyl aralkyl,
cycloalkyl and aryl optionally substituted with one or more
radicals selected from alkylthio, nitro and alkylsulfonyl; and
wherein each R.sup.4 is independently selected from the group
consisting of H, halo, alkyl, aralkyl, alkoxy, aryloxy,
heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy,
alkylamino, arylamino, aralkylamino, heteroarylamino,
heteroarylalkylamino, nitro, amino, aminosulfonyl,
alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,
aralkylaminosulfonyl, heteroaralkylaminosulfonyl- ,
heterocyclosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl,
optionally substituted aryl, optionally substituted heteroaryl,
aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl,
and alkylcarbonyl; wherein R.sup.4 together with the carbon atoms
to which it is attached and the remainder of ring E forms a
naphthyl radical; or a pharmaceutically acceptable salt or an
isomer or a prodrug thereof.
11. The method of claim 10, wherein: n is an integer which is 0, 1,
2, 3 or 4; G is O, S or NR.sup.b; R.sup.1 is H; R.sup.b is alkyl;
R.sup.2 is selected from the group consisting of carboxyl,
aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
R.sup.3 is selected from the group consisting of haloalkyl, alkyl,
aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl,
cycloalkyl, and aryl each is independently optionally substituted
with one or more radicals selected from the group consisting of
alkylthio, nitro and alkylsulfonyl; and each R.sup.4 is
independently selected from the group consisting of hydrido, halo,
alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino,
aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino,
aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl,
heteroarylaminosulfonyl, aralkylaminosulfonyl,
heteroaralkylaminosulfonyl- , heterocyclosulfonyl, alkylsulfonyl,
optionally substituted aryl, optionally substituted heteroaryl,
aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl,
and alkylcarbonyl; or wherein R.sup.4 together with ring E forms a
naphthyl radical.
12. The method of claim 10, wherein: n is an integer which is 0, 1,
2, 3 or 4; G is oxygen or sulfur; R.sup.1 is H; R.sup.2 is
carboxyl, lower alkyl, lower aralkyl or lower alkoxycarbonyl;
R.sup.3 is lower haloalkyl, lower cycloalkyl or phenyl; and each
R.sup.4 is H, halo, lower alkyl, lower alkoxy, lower haloalkyl,
lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl,
lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl,
6-membered heteroarylalkylaminosulfonyl, lower
aralkylaminosulfonyl, 5-membered nitrogen-containing
heterocyclosulfonyl, 6-membered-nitrogen containing
heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted
phenyl, lower aralkylcarbonyl, or lower alkylcarbonyl; or wherein
R.sup.4 together with the carbon atoms to which it is attached and
the remainder of ring E forms a naphthyl radical.
13. The method of claim 10, wherein: R.sup.2 is carboxyl; R.sup.3
is lower haloalkyl; and each R.sup.4 is H, halo, lower alkyl, lower
haloalkyl, lower haloalkoxy, lower alkylamino, amino,
aminosulfonyl, lower alkylaminosulfonyl, 5-membered
heteroarylalkylaminosulfonyl, 6-membered
heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower
alkylsulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl,
optionally substituted phenyl, lower aralkylcarbonyl, or lower
alkylcarbonyl; or wherein R.sup.4 together with ring E forms a
naphthyl radical.
14. The method of claim 10, wherein: n is an integer which is 0, 1,
2, 3 or 4; R.sup.3 is fluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
difluoromethyl, or trifluoromethyl; and each R.sup.4 is H, chloro,
fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl,
isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy,
tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy,
amino, N,N-dimethylamino, N,N-diethylamino,
N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl- ,
N-(2-furylmethyl)aminosulfonyl, nitro, N,N-dimethylaminosulfonyl,
aminosulfonyl, N-methylaminosulfonyl, N-ethylsulfonyl,
2,2-dimethylethylaminosulfonyl, N,N-dimethylaminosulfonyl,
N-(2-methylpropyl)aminosulfonyl, N-morpholinosulfonyl,
methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl,
phenylacetyl or phenyl; or wherein R.sup.4 together with the carbon
atoms to which it is attached and the remainder of ring E forms a
naphthyl radical.
15. The method of claim 10 wherein the cyclooxygenase-2 selective
inhibitor comprises a compound of the formula: 235G is oxygen or
sulfur; R.sup.8 is trifluoromethyl or pentafluoroethyl; R.sup.9 is
H, chloro, or fluoro; R.sup.10 is H, chloro, bromo, fluoro, iodo,
methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl,
dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl,
benzylaminosulfonyl, phenylethylaminosulfonyl,
methylpropylaminosulfonyl, methylsulfonyl, or morpholinosulfonyl;
R.sup.11 is H, methyl, ethyl, isopropyl, tert-butyl, chloro,
methoxy, diethylamino, or phenyl; and R.sup.12 is H, chloro, bromo,
fluoro, methyl, ethyl, tert-butyl, methoxy, or phenyl
16. The method of claim 10 wherein the cyclooxygenase-2 selective
inhibitor, pharmaceutically acceptable salt, isomer or prodrug
thereof is selected from the group consisting of:
6-chloro-2-trifluoromethyl-2H-1-be- nzopyran-3-carboxylic acid;
6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzo- pyran-3-carboxylic
acid; 8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyr-
an-3-carboxylic acid;
6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H--
1-benzopyran-3-carboxylic acid;
6-chloro-8-(1-methylethyl)-2-trifluorometh-
yl-2H-1-benzopyran-3-carboxylic acid;
2-trifluoromethyl-3H-naphthopyran-3-- carboxylic acid;
7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-
-carboxylic acid;
6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid; 7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid; 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid; 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid; 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid; 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid; 2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid;
6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid; 6-bromo-8-methoxy-2-tri
fluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-car-
boxylic acid;
6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyra-
n-3-carboxylic acid;
6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benz-
opyran-3-carboxylic acid;
6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H--
1-benzopyran-3-carboxylic acid;
6-[(1,1-dimethylethyl)aminosulfonyl]-2-tri-
fluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-[(2-methylpropyl)aminosu-
lfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopy-
ran-3-carboxylic acid;
6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-- carboxylic
acid; 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxyli- c
acid;
8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxyl-
ic acid;
6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopy-
ran-3-carboxylic acid;
6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromet-
hyl-2H-1-benzopyran-3-carboxylic acid;
6-iodo-2-trifluoromethyl-2H-1-benzo- pyran-3-carboxylic acid;
7-(1,1-dimethylethyl)-2-pentafluoroethyl-2H-1-ben-
zopyran-3-carboxylic acid; and
6-chloro-2-trifluoromethyl-2H-1-benzothiopy- ran-3-carboxylic
acid.
17. The method of claim 10 wherein the cyclooxygenase-2 selective
inhibitor, pharmaceutically acceptable salt or prodrug thereof is
selected from the group consisting of formulas: 236237238and any
combination thereof.
18. The method of claim 1 wherein the cyclooxygenase inhibitor
comprises a composition of the formula: 239wherein A is selected
from the group consisting of partially unsaturated or unsaturated
heterocyclyl and partially unsaturated or unsaturated carbocyclic
rings; wherein R.sup.1 is selected from the group consisting of
heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R.sup.1 is
optionally substituted at a substitutable position with one or more
radicals selected from alkyl, haloalkyl, cyano, carboxyl,
alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,
alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo,
alkoxy and alkylthio; wherein R.sup.2 is selected from the group
consisting of methyl or amino; and wherein R.sup.3 is selected from
the group consisting of a radical selected from H, halo, alkyl,
alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl,
heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl,
aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl,
heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl,
alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl,
aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl,
N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,
alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino,
N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino,
aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,
N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy,
aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,
aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl, N-alkyl-N-arylaminosulfonyl; or a pharmaceutically
acceptable salt or prodrug thereof.
19. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor pharmaceutically acceptable salt or prodrug thereof is
selected from the group consisting of: 240241and any combination
thereof.
20. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor or a pharmaceutically acceptable salt or prodrug thereof
is selected from the group consisting of: 242243244245246and any
combination thereof.
21. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises: 247or a pharmaceutically acceptable salt or
prodrug thereof.
22. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises: 248or a pharmaceutically acceptable salt or
prodrug thereof.
23. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises
4-[4-(methyl)-sulfonyl)phenyl]-3-phenyl-2(5H)-furanone, or a
pharmaceutically acceptable salt or prodrug thereof.
24. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises, 4-(5-methyl-3-phenyl-4-isoxazolyl), or a
pharmaceutically acceptable salt or prodrug thereof.
25. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises,
2-(6-methylpyrid-3-yl)-3-(4-methylsulfonylphenyl)-5-chloropyri-
dine, or a pharmaceutically acceptable salt or prodrug thereof.
26. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises,
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl], or a
pharmaceutically acceptable salt or prodrug thereof.
27. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises,
N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl], or a
pharmaceutically acceptable salt or prodrug thereof.
28. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises,
4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide, or a pharmaceutically acceptable salt or
prodrug thereof.
29. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises,
(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxy- lic
acid, or a pharmaceutically acceptable salt or prodrug thereof.
30. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises,
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridzainone, or a pharmaceutically
acceptable salt or prodrug thereof.
31. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises a compound of the formula: 249wherein: R.sup.16
is methyl or ethyl; R.sup.17 is chloro or fluoro; R.sup.18 is
hydrogen or fluoro; R.sup.19 is hydrogen, fluoro, chloro, methyl,
ethyl, methoxy, ethoxy or hydroxy; R.sup.20 is hydrogen or fluoro;
R.sup.21 is chloro, fluoro, trifluoromethyl or methyl, provided
that R.sup.17, R.sup.18, R.sup.19 and R.sup.20 are not all fluoro
when R.sup.16 is ethyl and R.sup.19 is H; or an isomer, a
pharmaceutically acceptable salt, ester, or prodrug thereof.
32. The method of claim 31 wherein: R.sup.16 is ethyl; R.sup.17 and
R.sup.19 are chloro; R.sup.18 and R.sup.20 are hydrogen; and and
R.sup.21 is methyl.
33. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises a compound of the formula: 250wherein: X is O
or S; J is a carbocycle or a heterocycle; R.sup.22 is
NHSO.sub.2CH.sub.3 or F; R.sup.23 is H, NO.sub.2, or F; and
R.sup.24 is H, NHSO.sub.2CH.sub.3, or
(SO.sub.2CH.sub.3)C.sub.6H.sub.4; or an isomer, a pharmaceutically
acceptable salt, an ester, or a prodrug thereof.
34. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises a compound of the formula: 251wherein: T and M
independently are phenyl, naphthyl, a radical derived from a
heterocycle comprising 5 to 6 members and possessing from 1 to 4
heteroatoms, or a radical derived from a saturated hydrocarbon ring
having from 3 to 7 carbon atoms; Q.sup.1, Q.sup.2, L.sup.1 or
L.sup.2 are independently hydrogen, halogen, lower alkyl having
from 1 to 6 carbon atoms, trifluoromethyl, or lower methoxy having
from 1 to 6 carbon atoms; and at least one of Q.sup.1, Q.sup.2,
L.sup.1 or L.sup.2 is in the para position and is --S(O).sub.n--R,
wherein n is 0, 1, or 2 and R is a lower alkyl radical having 1 to
6 carbon atoms or a lower haloalkyl radical having from 1 to 6
carbon atoms, or an --SO.sub.2NH.sub.2; or, Q.sup.1 and Q.sup.2 are
methylenedioxy; or L.sup.1 and L.sup.2 are methylenedioxy; and
R.sup.25, R.sup.26, R.sup.27, and R.sup.28 are independently
hydrogen, halogen, lower alkyl radical having from 1 to 6 carbon
atoms, lower haloalkyl radical having from 1 to 6 carbon atoms, or
an aromatic radical selected from the group consisting of phenyl,
naphthyl, thienyl, furyl and pyridyl; or, R.sup.25 and R.sup.26 are
0; or R.sup.27 and R.sup.28 are 0; or, R.sup.25, R.sup.26, together
with the carbon atom to which they are attached, form a saturated
hydrocarbon ring having from 3 to 7 carbon atoms; or, R.sup.27,
R.sup.28, together with the carbon atom to which they are attached,
form a saturated hydrocarbon ring having from 3 to 7 carbon atoms;
or an isomer, a pharmaceutically acceptable salt, an ester, or a
prodrug thereof.
35. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor, pharmaceutically acceptable salt, isomer, or prodrug
thereof is selected from the group consisting of:
3-[(3-Chloro-phenyl)-(4-methane-
sulfony-phenyl)-methylene]-dihydro-furan-2-one;
8-acetyl-3-(4-fluorophenyl-
)-2-(4-methylsulfonyl)phenyl-imidazo[1,2-a);
5,5-dimethyl-4-(4-methylsulfo- nyl)phenyl-3-phenyl-2-(5H)-furanone;
5-(4-fluorophenyl)-1-[4-(methylsulfon-
yl)phenyl]-3-(trifluoromethyl)pyrazole;
4-(4-fluorophenyl)-5-[4-(methylsul-
fonyl)phenyl]-1-phenyl-3-(trifluoromethyl)pyrazole;
4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonam-
ide; 4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;
4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonami-
de;
4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfona-
mide;
4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl)benzene-
sulfonamide;
4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)benzenesulfonamide;
4-[5-(4-chlorophenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide;
4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide;
4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]ben-
zenesulfonamide;
4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyr-
azol-1-yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H--
pyrazol-1-yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-
-1-yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyr-
azol-1-yl]benzenesulfonamide;
4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-y- l]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1-
H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-fluoro-4-methoxyphenyl)-3-(trif-
luoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-phenyl-1H-p- yrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-
-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-(N,N-dimethylamino)phenyl)-3-(tr-
ifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
5-(4-fluorophenyl)-6-[4-
-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
4-[6-(4-fluorophenyl)spiro[2- .4]hept-5-en-5-yl]benzenesulfonamide;
6-(4-fluorophenyl)-7-[4-(methylsulfo-
nyl)phenyl]spiro[3.4]oct-6-ene;
5-(3-chloro-4-methoxyphenyl)-6-[4-(methyls-
ulfonyl)phenyl]spiro[2.4]hept-5-ene;
4-[6-(3-chloro-4-methoxyphenyl)spiro[-
2.4]hept-5-en-5-yl]benzenesulfonamide;
5-(3,5-dichloro-4-methoxyphenyl)-6--
[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
5-(3-chloro-4-fluorophenyl-
)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;
2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-
thiazole;
2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-
thiazole;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino)thiazole;
2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)p-
henyl]thiazole;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluorom-
ethylthiazole;
1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopen-
ta-2,4-dien-3-yl]benzene;
4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-
-dien-3-yl]benzenesulfonamide;
5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phe-
nyl]spiro[2.4]hepta-4,6-diene;
4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-di-
en-5-yl]benzenesulfonamide;
6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfo-
nyl)phenyl]-pyridine-3-carbonitrile;
2-bromo-6-(4-fluorophenyl)-5-[4-(meth-
ylsulfonyl)phenyl]-pyridine-3-carbonitrile;
6-(4-fluorophenyl)-5-[4-(methy-
lsulfonyl)phenyl]-2-phenyl-pyridine-3-carbonitrile;
4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenes-
ulfonamide;
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1--
yl]benzenesulfonamide;
4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H--
imidazol-1-yl]benzenesulfonamide;
3-[1-[4-(methylsulfonyl)phenyl]-4-(trifl-
uoromethyl)-1H-imidazol-2-yl]pyridine;
2-[1-[4-(methylsulfonyl)phenyl-4-(t-
rifluoromethyl)-1H-imidazol-2-yl]pyridine;
2-methyl-4-[1-[4-(methylsulfony-
l)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
2-methyl-6-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-
-yl]pyridine;
4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol--
1-yl]benzenesulfonamide;
2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)pheny-
l]-4-(trifluoromethyl)-1H-imidazole;
4-[2-(4-methylphenyl)-4-(trifluoromet-
hyl)-1H-imidazol-1-yl]benzenesulfonamide;
2-(4-chlorophenyl)-1-[4-(methyls-
ulfonyl)phenyl]-4-methyl-1H-imidazole;
2-(4-chlorophenyl)-1-[4-(methylsulf-
onyl)phenyl]-4-phenyl-1H-imidazole;
2-(4-chlorophenyl)-4-(4-fluorophenyl)--
1-[4-(methylsulfonyl)phenyl]-1H-imidazole;
2-(3-fluoro-4-methoxyphenyl)-1--
[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazole;
1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole;
2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imid-
azole;
4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl-
]benzenesulfonamide;
2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phen-
yl]-4-(trifluoromethyl)-1H-imidazole;
4-[2-(3-fluoro-5-methylphenyl)-4-(tr-
ifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imid-
azole;
4-[2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide;
1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethy-
l-1H-imidazole;
4-[2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]b-
enzenesulfonamide;
4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl]benzenes-
ulfonamide;
4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol--
1-yl]benzenesulfonamide;
1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)p-
henyl]-5-(trifluoromethyl)-1H-pyrazole;
4-[1-ethyl-4-(4-fluorophenyl)-5-(t-
rifluoromethyl)-1H-pyrazol-3-yl]benzenesulfonamide;
N-phenyl-[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromet-
hyl)-1H-pyrazol-1-yl]acetamide; ethyl
[4-(4-fluorophenyl)-3-[4-(methylsulf-
onyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate;
4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-1H-pyra-
zole;
4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-5--
(trifluoromethyl)pyrazole;
1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl-
)phenyl]-5-(trifluoromethyl)-1H-pyrazole;
5-(4-fluorophenyl)-4-(4-methylsu-
lfonylphenyl)-2-trifluoromethyl-1H-imidazole;
4-[4-(methylsulfonyl)phenyl]-
-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-imidazole;
5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromet-
hyl)pyridine;
2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(-
trifluoromethyl)pyridine;
5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]--
2-(2-propynyloxy)-6-(trifluoromethyl)pyridine;
2-bromo-5-(4-fluorophenyl)--
4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;
4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;
1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole;
4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide;
4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide;
1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene-
; 1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene-
;
1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)ben-
zene;
4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonamid-
e;
1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)b-
enzene;
4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonam-
ide; 4-[2-(4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;
4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide;
1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl]benzenesulfonamide;
1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzen-
e;
4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;
4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]benzenesulfonamide;
ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)
phenyl]oxazol-2-yl]-2-benzyl-- acetate;
2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]ace-
tic acid;
2-(tert-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]ox-
azole;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole;
4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole;
4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzenesulfo-
namide;
6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-
-carboxylic acid;
6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-ca- rboxylic
acid; 5,5-dimethyl-3-(3-fluorophenyl)-4-methylsulfonyl-2(5H)-fura-
none; 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic
acid;
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulf-
onamide;
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-y-
l]benzenesulfonamide;
3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-
-imidazol-2-yl]pyridine;
2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-triflu-
oromethyl-1H-imidazol-2-yl]pyridine;
4-[2-(5-methylpyridin-3-yl)-4-(triflu-
oromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
4-[5-methyl-3-phenylisoxaz- ol-4-yl]benzenesulfonamide;
4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benze- nesulfonamide;
[2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzen-
esulfonamide; 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide;
4-[5-(2-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzenesulfo-
namide; [2-(2-chloro-6-fluoro-phenylamino)-5-methyl-phenyl]-acetic
acid; N-(4-Nitro-2-phenoxy-phenyl)-methanesulfonamide or
nimesulide;
N-[6-(2,4-difluoro-phenoxy)-1-oxo-indan-5-yl]-methanesulfonamide;
N-[6-(2,4-Difluoro-phenylsulfanyl)-1-oxo-1H-inden-5-yl]-methanesulfonamid-
e, soldium salt;
N-[5-(4-fluoro-phenylsulfanyl)-thiophen-2-yl]-methanesulf- onamide;
3-(3,4-Difluoro-phenoxy)-4-(4-methanesulfonyl-phenyl)-5-methyl-5--
(2,2,2-trifluoroethyl)-5H-furan-2-one;
(5Z)-2-amino-5-[[3,5-bis(1,1-dimeth-
ylethyl)-4-hydroxyphenyl]methylene]-4(5H)-thiazolone;
N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfonami-
de; (6aR,
10aR)-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,-
6-dimethyl-6H-dibenzo[b,d]pyran-9-carboxylic acid;
4-[[3,5-bis(1,1-dimethy-
lethyl)-4-hydroxyphenyl]methylene]dihydro-2-methyl-2H-1,2-oxazin-3(4H)-one-
; 6-dioxo-9H-purin-8-yl-cinnamic acid;
4-[4-(methyl)-sulfonyl)phenyl]-3-ph- enyl-2(5H)-furanone;
4-(5-methyl-3-phenyl-4-isoxazolyl);
2-(6-methylpyrid-3-yl)-3-(4-methylsulfonylphenyl)-5-chloropyridine;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl];
N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl];
4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide;
(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carbox- ylic
acid;
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3 (2H)-pyridzainone;
2-trifluoromethyl-3H-naptho[2,1-b]p- yran-3-carboxylic acid;
6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2-
H-1-benzopyran-3-carboxylic acid; and
[2-(2,4-dichloro-6-ethyl-3,5-dimethy-
l-phenylamino)-5-propyl-phenyl]-acetic acid.
36. The method of claim 1 wherein the amyloid beta vaccine is a
peptide vaccine.
37. The method of claim 1 wherein the amyloid beta vaccine is a
nucleic acid vaccine.
38. The method of claim 36 wherein the amyloid beta vaccine
comprises at least one amyloid beta peptide selected from Abeta
(1-43), or a fragment, variant, or analog thereof.
39. The method of claim 38 wherein the amyloid beta peptide is
selected from the group consisting of Abeta (1-42), Abeta (1-43),
Abeta (1-40), Abeta (1-39), Abeta (1-41), Abeta (1-28), Abeta
(1-16), Abeta (25-35), Abeta (29-39), Abeta (29-40), Abeta (29-41),
Abeta (29-42), Abeta (29-43), Abeta (26-42), Abeta (26-43), and
Abeta (35-43).
40. The method of claim 39 wherein the amyloid beta peptide is
Abeta (1-42).
41. The method of claim 38 wherein the amyloid beta vaccine further
comprises an adjuvant.
42. The method of claim 41 wherein the adjuvant is aluminum
hydroxide.
43. The method of claim 41 wherein the adjuvant is aluminum
phosphate.
44. The method of claim 36 wherein the amyloid beta vaccine is a
monovalent vaccine.
45. The method of claim 36 wherein the amyloid beta vaccine is a
multivalent vaccine.
46. The method of claim 1 wherein the amyloid beta vaccine is
administered prior to the administration of the Cox-2
inhibitor.
47. The method of claim 1 wherein the Cox-2 inhibitor is
administered during time intervals between each amyloid beta
vaccination.
48. The method of claim 1 wherein the amyloid beta vaccine is
administered following the administration of the Cox-2
inhibitor.
49. The method of claim 1 wherein the amyloid beta vaccine is
administered for the life of the subject.
50. The method of claim 1 wherein the subject is a mammal.
51. The method of claim 50 wherein the mammal is a human being.
52. A composition comprising an amyloid beta vaccine and a
cyclooxygenase-2 selective inhibitor or a pharmaceutically
acceptable salt or prodrug thereof.
53. The composition of claim 52 wherein the cyclooxygenase-2
selective inhibitor comprises a chromene compound.
54. The composition of claim 53 wherein the chromene compound is a
benzopyran or substituted benzopyran analog.
55. The composition of claim 54 wherein the benzopyran or
substituted benzopyran analog is selected from the group consisting
of benzothiopyrans, dihydroquinolines and dihydronaphthalenes.
56. The composition of claim 52 wherein the cyclooxygenase-2
selective inhibitor comprises a tricyclic compound.
57. The composition of claim 56 wherein the tricyclic compound
comprises a benzenesulfonamide or methylsulfonylbenzene.
58. The composition of claim 52 wherein the cyclooxygenase-2
selective inhibitor comprises a phenyl acetic acid derivative.
59. The composition of claim 52 wherein the amyloid beta vaccine is
a peptide vaccine.
60. The composition of claim 52 wherein the amyloid beta vaccine is
a nucleic acid vaccine.
61. The composition of claim 59 wherein the amyloid beta vaccine
comprises at least one amyloid beta peptide selected from Abeta
(1-43), or a fragment, variant, or analog thereof.
62. The composition of claim 61 wherein the amyloid beta peptide is
selected from the group consisting of Abeta (1-42), Abeta (1-43),
Abeta (1-40), Abeta (1-39), Abeta (1-41), Abeta (1-28), Abeta
(1-16), Abeta (25-35), Abeta (29-39), Abeta (29-40), Abeta (29-41),
Abeta (29-42), Abeta (29-43), Abeta (26-42), Abeta (26-43), and
Abeta (35-43).
63. The composition of claim 62 wherein the amyloid beta peptide is
Abeta (1-42).
64. The composition of claim 61 wherein the amyloid beta vaccine
further comprises an adjuvant.
65. The composition of claim 64 wherein the adjuvant is aluminum
hydroxide.
66. The composition of claim 64 wherein the adjuvant is aluminum
phosphate.
67. The composition of claim 59 wherein the amyloid beta vaccine is
a monovalent vaccine.
68. The composition of claim 59 wherein the amyloid beta vaccine is
a multivalent vaccine.
69. The method of claim 1 wherein the vaccine is administered by a
route selected from the group consisting of oral, intramuscular,
intravenous, subcutaneous, intradermal, and intraperitoneal.
70. The method of claim 1 wherein the cyclooxygenase-2 selective
inhibitor comprises a compound of the formula: 252
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATION
[0001] This patent claims priority to U.S. Provisional Application
Serial No. 60/402,760, filed Aug. 12, 2002, U.S. Provisional
Application Serial No. 60/402,778, filed Aug. 12, 2002, U.S.
Provisional Application Serial No. 60/402,674, filed Aug. 12, 2002,
U.S. Provisional Application Serial No. 60/402,676, filed Aug. 12,
2002, U.S. Provisional Application Serial No. 60/402,655, filed
Aug. 12, 2002, U.S. Provisional Application Serial No. 60/402,773,
filed Aug. 12, 2002, and U.S. Provisional Application Serial No.
60/402,675, filed Aug. 12, 2002. The entire text of this
provisional application is incorporated by reference into the
present application.
FIELD OF THE INVENTION
[0002] The present invention provides compositions and methods for
the treatment of Alzheimer's disease. More particularly, the
invention is directed toward a combination therapy for the
treatment or prevention of Alzheimer's disease comprising
administering to a subject a cyclooxygenase-2 inhibitor in
combination with amyloid vaccination.
BACKGROUND OF THE INVENTION
[0003] Alzheimer's disease (AD) causes progressive dementia with
consequent formation of amyloid plaques, neurofibrillary tangles,
gliosis and neuronal loss. As one of the leading causes of death in
industrialized countries, AD affects 5-11% of the population over
the age of 65 and 30% of those over the age of 85. The estimated
cost of caring for the approximate 2.5-4.0 million AD patients in
the U.S. exceeded $60 billion in 1991 alone. It is further
estimated that AD related costs would dramatically increase
worldwide as the geriatric population grows.
[0004] Alzheimer's disease occurs in both genetic and sporadic
forms, however clinical course and pathological features of both
forms are quite similar. Three genes have been discovered which,
when mutated, cause an autosomal dominant form of Alzheimer's
disease. These encode the amyloid protein precursor (APP) and two
proteins, presenilin-1 (PS1) and presenilin-2 (PS2), which are
structurally and functionally related. Different forms of APP have
been isolated and range in size from 695-770 amino acids, but all
of them localize to the cell surface and have a single C-terminal
transmembrane domain. Examples of specific isotypes of APP
currently known to exist in humans include the 695-amino acid
polypeptide described by Kang et. al. (1987), Nature 325: 733-736
which is designated as the "normal" APP; the 751 amino acid
polypeptide described by Ponte et al. (1988), Nature 331: 525-527
(1988) and Tanzi et al. (1988), Nature 331: 528-530; and the 770
amino acid polypeptide described by Kitaguchi et. al. (1988),
Nature 331: 530-532.
[0005] Mutations in any of the three proteins (APP, PS1 or PS2)
have been observed to enhance proteolytic processing of APP via an
intracellular pathway that produces amyloid beta peptide (A.beta.
peptide, or sometimes here as Abeta), a peptide that is the primary
component of amyloid plaques in AD. Naturally-occurring
.beta.-amyloid peptide shows some heterogeneity since it can be
39-43 amino acid residues in length but generally it begins at an
aspartic acid position 672 of APP-770.
[0006] The A.beta. peptide is derived from a region adjacent to and
containing a portion of the transmembrane domain of APP. Normally,
processing of APP at the .alpha.-secretase site cleaves the
midregion of the A.beta. sequence adjacent to the membrane and
releases the soluble, extracellular domain of APP from the cell
surface. This .alpha.-secretase APP processing creates soluble
APP-.alpha., which is normal and not thought to contribute to AD.
Pathological processing of APP at the .beta.- and y-secretase
sites, which are located N-terminal and C-terminal to the
.alpha.-secretase site, respectively, produces a very different
result than processing at the a site. Sequential processing at the
.beta.- and .gamma.-secretase sites releases the A.beta. peptide,
and can occur in both the endoplasmic reticulum (in neurons) and in
the endosomal/lysosomal pathway after reinternalization of cell
surface APP (in all cells).
[0007] The amyloid plaque is the focus of complex cellular
reactions involving the activation of both microglia and astrocytes
adjacent to the amyloid plaque. Microglia are the most abundant and
prominent cellular component of the plaque, where they generally
exhibit a "reactive" or "activated" phenotype. Microglia are the
principal immune cells in the brain, and are morphologically and
functionally indistinguishable from macrophages. As seen with
macrophages, the activated phenotype of microglia is associated
with elevated expression of a number of cell surface molecules,
including MHC class II antigens, CD45, complement receptors CR3 and
CR4, immunoglobulin receptors FcgRI and FcgRII, and ICAM-1.
Furthermore, activated microglia, like activated macrophages,
secrete a diverse range of acute phase proteins including
.alpha.-antichymotrypsin, .alpha.-antitrypsin, serum amyloid P,
C-reactive protein, and complement components, among others (McGeer
and Rogers, Neurology 42:447 [1992]). Importantly, activation of
microglia results in the synthesis and secretion of proinflammatory
cytokines IL-1.beta., IL-6, and TNF-.alpha. and macrophage
chemotactic protein-1.
[0008] In addition to the above-mentioned features, a substantial
decrease in cholinergic functioning has been well-documented in AD
patients. Both the content of acetylcholine and the activity of
choline acetyltransferase are reduced due to degeneration in the
basal forebrain. Consistent with the "cholinergic hypothesis of
AD", which states that there is a direct relationship between the
loss of cholinergic function in the brain and the degree of
cognitive impairment (Bartus et al., Science, 217:408-414, 1982),
anticholinergic drugs are known to impair memory and cognitive
functioning in a similar fashion as AD (Sunderland et al., Arch Gen
Psych, 44:418-425, 1987). This correlation has provided cues for
potential AD therapies.
[0009] Accordingly, one of the current treatments for AD involves
the use of cholinesterase inhibitors, also known as
anticholinesterases. These agents inhibit the hydrolytic
degradation of acetylcholine by the enzyme acetylcholinesterase
(AchE) in the synaptic cleft, thus potentiating cholinergic
transmission (Norberg A. and Svensson A. L., Drug Saf, 19:465-480,
1998). Tacrine (Cognex), a nonselective reversible cholinesterase
inhibitor was the first drug in this class approved by the FDA for
use in AD in 1993. However, this drug has a short half-life,
requiring multiple daily doses and also exhibits hepatotoxic
effects in a number of patients. Donepezil (Aricept) was approved
in 1996 and has a longer half-life, allowing for once/day dosing
and shows almost no hepatotoxicity and relatively low incidence of
gastrointestinal side effects. It is now widely utilized to treat
patients with mild to moderately severe AD patients since
controlled trials have shown that the drug can delay AD-associated
deterioration.
[0010] Rivastigmine is a relatively selective, pseudo-irreversible
cholinesterase inhibitor with a 10-hour duration of action (Forerte
et al., European J Neurol., 6:423-429, 1999); however, it does
exhibit some gastrointestinal side effects and weight loss.
Galantamine is a reversible competitive inhibitor as well as a
modulator of nicotinic cholinergic receptors, and is currently
approved for use for AD in Austria (Schenk et al., Abstracts from
the 7.sup.th International Conference on Alzheimer's Disease and
Related Disorders, Neurobiol of Aging, 21(1S)S134, 2000). Other
cholinesterase inhibitors are either in clinical trials or have
been withdrawn from consideration due to adverse effects. For
example, metrifonate was withdrawn from consideration during Phase
III trials, where it was found to cause leg cramps and muscle
cramps (Morris et al., Neurology, 50:1222-1230, 1998).
[0011] Some of the other treatments are based on the fact that
monoamine oxidase B (MAO-B) activity is increased in AD and may
cause an increase in oxidative deamination of monoamines. As a
result of such deamination, hydrogen peroxide and other free
radicals may be formed, resulting in toxic effects on neuronal
membranes and loss of neurons. Selegiline, a selective MAO-B
inhibitor, and alpha-tocopherol (vitamin E) are both antioxidants
and appear to have therapeutic effect on AD treatment. In a study
enrolling over 300 AD patients, selegeline and vitamin E were both
found to slow the progression of the disease (Sano et al., NEJM,
336:1216-1222, 1997).
[0012] As mentioned previously, the lesions of AD are characterized
by the presence of numerous inflammatory proteins. Accordingly, a
number of studies have started to evaluate the efficacy of
anti-inflammatory drugs in treatment of AD. For example, a
controlled 6-month investigation by Rogers, J. et al., in Neurology
(August 1993, 43:1609) involved the administration of 100-150 mg
indomethacin (a non-steroidal anti-inflammatory drug, NSAID) or
placebo to mild or moderately impaired Alzheimer's disease
patients. The study concluded, based on a battery of cognitive
tests, that the indomethacin treatment appeared to protect the
patients receiving indomethacin from the degree of cognitive
decline exhibited by the patients receiving placebo. Furthermore,
S-2474, an NSAID that inhibits cyclooxygenase-2 significantly
prevented neurons from Abeta (25-35) and Abeta (1-40) induced cell
death (Yagami et al., British Journal of Pharmacology,
134(3):673-681, October 2001). Kadoyama et al. used mouse
neuroblastoma and rat glioma hybrid NG108-15 cells to examine the
role of COX-2 in APP production and secretion. For the experiment,
they either mock-transfected the cells or stably transfected them
with human Cox-2. Cells expressing Cox-2 exhibited 3-to 4-fold
increases in both COX activity and prostaglandin E2 production.
Notably, the mRNA level of amyloid precursor protein (APP) was
elevated by approximately 2-fold in the Cox-2 expressing cells. In
the same study, a selective Cox-2 inhibitor (JTE-522) and a
nonselective Cox inhibitor (indomethacin) suppressed production of
amyloid .beta.-peptide and a secreted form of APP by inhibition of
APP mRNA level (Kadoyama et al., Biochem. Biophys. Res. Commun.,
281(2):483-490, 2001).
[0013] An alternative treatment that is currently in development
involves vaccination with a synthetic form of the naturally
occurring .beta.-amyloid protein. In animals, immunization of young
mice with Abeta prevented the appearance of amyloid plaques and
other neuropathologic changes characteristic of AD (Reisberg et
al., Neuobiol of Aging, 21(1S)S275, 2000). In addition, a single
dose of an investigational Abeta vaccine (AN-1792) was well
tolerated in 24 patients with early onset AD during a six-week
period following injection (Schenk et al., Nature 400 (6740),
pp.173-177, 1999). It is unclear how vaccination confers protection
against AD but it is believed that the mechanism may involve 1)
production of anti-.beta. amyloid antibodies that can neutralize or
deplete Abeta and/or 2) activation of microglia that can
phagocytose deposited Abeta (Morgan et al., Nature, Vol. 408, no.
21, p. 982-985, December 2000). The hypothesis about activation of
microglia is not as widely accepted as the hypothesis of antibody
production since relatively modest Abeta clearance has been
detected following vaccination.
[0014] A study by Casamenti et al. examined the effect of Cox-2
inhibitors on brain inflammation caused by an injection of
pre-aggregated Abeta (1-42) into nucleus basalis (NB) of adult rats
(Casamneti et al., J. Neurochem., 77, Suppl. 1, 10, 2001). In the
experiment, rofecoxib attenuated microglial and astrocytic
activation. As reported, however, Abeta vaccine was administered
directly into the central nervous system (CNS). Another study by
the same group (Scali et al., Society for Neuroscience Abstracts,
Vol. 26, No. 1-2, 2000, ISSN:0190-5295) investigated the role of
non-selective (ibuprofen) and selective Cox-2 inhibitors (rofecoxib
and nimesulide) on glia reaction, inducible nitric oxyde synthase
(iNOS) production, mitogen activated protein kinase (MAPK)
expression and prostaglandin E2 (PGE2) levels during brain
inflammation. The inflammatory reaction was induced either by
injecting excitotoxin quisqualic acid (QUIS) or beta-amyloid
peptide (1-42) intracerebrally. Once again, the Abeta injection was
administered directly into the CNS. Seven days following the
injection, both nimesulide and ibuprofen treatment (each
administered once a day) attenuated microglia reaction and reduced
the number of iNOS-positive cells but had no effect on astrocytic
reaction. This is in contradiction with the previously-mentioned
study where a selective Cox-2 inhibitor was able to attenuate
astrocytic reaction. In addition, it is unclear whether the brain
inflammation caused by the injection of QUIS or Abeta exhibits the
same characteristics as observed in AD. Thus, it is difficult to
determine from these studies the exact effects of Cox-2 inhibitors
or amyloid beta peptide injection on Alzheimer's disease.
[0015] It is clear from the presented data that there is a need for
novel and/or improved treatments for Alzheimer's disease due to the
paucity of currently available therapies. As the life expectancy
increases and the number of the elderly increases as well, the need
for different treatments in management and treatment of AD patients
is becoming more pronounced.
SUMMARY OF THE INVENTION
[0016] Among the several aspects of the invention is a method and a
composition for the treatment or prevention of Alzheimer's disease
in a subject. The composition comprises a cyclooxygenase-2
selective inhibitor and an amyloid beta vaccine, and the method
comprises administering to the subject a cyclooxygenase-2 selective
inhibitor or a pharmaceutically acceptable salt or prodrug thereof
and one or more doses of amyloid beta vaccines.
[0017] In one embodiment, the cyclooxygenase-2 selective inhibitor
comprises a compound of the formula: 1
[0018] wherein n is an integer which is 0, 1, 2, 3 or 4;
[0019] wherein G is O, S or NR.sup.a;
[0020] wherein R.sup.a is alkyl;
[0021] wherein R.sup.1 is selected from the group consisting of H
and aryl;
[0022] wherein R.sup.2 is selected from the group consisting of
carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and
alkoxycarbonyl;
[0023] wherein R.sup.3 is selected from the group consisting of
haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally
substituted with one or more radicals selected from alkylthio,
nitro and alkylsulfonyl; and
[0024] wherein each R.sup.4 is independently selected from the
group consisting of H, halo, alkyl, aralkyl, alkoxy, aryloxy,
heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy,
alkylamino, arylamino, aralkylamino, heteroarylamino,
heteroarylalkylamino, nitro, amino, aminosulfonyl,
alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,
aralkylaminosulfonyl, heteroaralkylaminosulfonyl- ,
heterocyclosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl,
optionally substituted aryl, optionally substituted heteroaryl,
aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl,
and alkylcarbonyl;
[0025] or wherein R.sup.4 together with the carbon atoms to which
it is attached and the remainder of ring E forms a naphthyl
radical;
[0026] or an isomer, a pharmaceutically acceptable salt, ester, or
prodrug thereof.
[0027] In another embodiment, the cyclooxygenase-2 selective
inhibitor or pharmaceutically acceptable salt or prodrug thereof
comprises a compound of the formula: 2
[0028] wherein A is selected from the group consisting of partially
unsaturated or unsaturated heterocyclyl and partially unsaturated
or unsaturated carbocyclic rings;
[0029] wherein R.sup.1 is selected from the group consisting of
heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R.sup.1 is
optionally substituted at a substitutable position with one or more
radicals selected from alkyl, haloalkyl, cyano, carboxyl,
alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,
alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo,
alkoxy and alkylthio;
[0030] wherein R.sup.2 is selected from the group consisting of
methyl or amino; and
[0031] wherein R.sup.3 is selected from the group consisting of a
radical selected from H, halo, alkyl, alkenyl, alkynyl, oxo, cyano,
carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio,
alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl,
cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl,
hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl,
aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl,
aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl,
alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl.
[0032] In another embodiment, the amyloid beta vaccine comprises
the amyloid peptide Abeta (1-43) or a fragment, variant or analog
thereof. In another embodiment, the amyloid beta vaccine can be
either monovalent or multivalent. In still another embodiment, the
vaccine, in addition to at least one amyloid beta peptide or
fragment thereof, comprises an adjuvant that contributes to the
immunogenicity of the vaccine. Preferably, the adjuvant is selected
from aluminum hydroxide or aluminum phosphate.
[0033] Other objects and features will be in part apparent and in
part pointed out hereinafter.
[0034] Abbreviations and Definitions
[0035] The term "prevention" includes either preventing the onset
of a clinically evident Alzheimer's disease or preventing the onset
of a preclinically evident stage of Alzheimer's disease in a
subject. This definition includes prophylactic treatment.
[0036] The terms "amyloid," "amyloid plaque," and "amyloid fibril"
refer generally to insoluble proteinaceous substances with
particular physical characteristics independent of the composition
of proteins or other molecules that are found in the substance.
Amyloid can be identified by its amorphous structure, eosinophilic
staining, changes in thioflavin fluorescence, and homogeneous
appearance. Protein or peptide components of amyloid are termed
herein "amyloid polypeptides," and as used herein refer to Abeta
polypeptides and fragments thereof.
[0037] The term ".beta.-amyloid peptide" or "Abeta" or "A.beta." as
used herein refers to an approximately 4.2 kD protein which, in the
brains of AD, Down's Syndrome, HCHWA-D (hereditary cerebral
hemorrhage with amyloidosis of the Dutch type) and some normal aged
subjects, forms the subunit of the amyloid filaments comprising the
senile (amyloid) plaques and the amyloid deposits in small cerebral
and meningeal blood vessels (amyloid angiopathy). Abeta peptide
that is found in amyloid plaques generally exists in several
isoforms that are about 39-43 amino acids long. Abeta can occur in
a filamentous polymeric form (in this form, it exhibits the
Congo-red and thioflavin-S dye-binding characteristics of amyloid),
but it can also occur in a non-filamentous form ("preamyloid" or
"amorphous" or "diffuse" deposits) in tissue, in which form no
detectable birefringent staining by Congo red occurs. Abeta was
first purified and a partial amino acid sequence reported in
Glenner and Wong (Biochem. Biophys. Res. Commun., 120:885-890,
1984). The isolation procedure and the sequence data for the first
28 amino acids are described in, e.g., U.S. Pat. No. 4,666,829. The
sequence of a 43-residue long A is disclosed, for example, in U.S.
Pat. No. 6,284,221. As used herein, "Abeta" peptide includes
fragments, analogs, and variants thereof.
[0038] The term "fragment" as used herein is intended to encompass
a portion of an amyloid peptide described herein.
[0039] The term "variant" as used herein refers to a molecule
substantially similar in structure and biological activity or
immunological properties to either the entire molecule or a
fragment thereof. Thus, provided that two molecules possess a
similar activity, they are considered variants even if the sequence
of their amino acid residues is not identical.
[0040] The term "analog" as used herein refers to a molecule
substantially similar in function to either the entire molecule or
to a fragment thereof. An analog may contain chemical moieties that
are not normally a part of the molecule, but that may, for example,
improve the molecule's half-life or decrease its toxicity. Moieties
capable of mediating such effects are disclosed in Remington's
Pharmaceutical Sciences (1980).
[0041] The phrase "therapeutically-effective" is intended to
qualify the amount of each agent which will achieve the goal of
improvement in disorder severity and the frequency of incidence
over no treatment or treatment of each agent by itself, while
avoiding adverse side effects typically associated with alternative
therapies.
[0042] The term "treatment" includes alleviation, elimination of
causation of or prevention of undesirable symptoms associated with
Alzheimer's disease. Treatment as used herein includes prophylactic
treatment.
[0043] The term "subject" for purposes of treatment includes any
human or animal subject who is afflicted or predisposed to
Alzheimer's disease. The subject can be a domestic livestock
species, a laboratory animal species, a zoo animal or a companion
animal. In one embodiment, the subject is a mammal. In a preferred
embodiment, the mammal is a human being.
[0044] The term "cyclooxygenase-2 selective inhibitor" denotes a
compound able to inhibit cyclooxygenase-2 without significant
inhibition of cyclooxygenase-1. Preferably, it includes compounds
that have a cyclooxygenase-2 IC.sub.50 of less than about 0.2 micro
molar, and also have a selectivity ratio of cyclooxygenase-2
inhibition over cyclooxygenase-1 inhibition of at least 50, and
more preferably of at least 100. Even more preferably, the
compounds have a cyclooxygenase-1 IC.sub.50 of greater than about 1
micro molar, and more preferably of greater than 10 micro molar.
Inhibitors of the cyclooxygenase pathway in the metabolism of
arachidonic acid used in the present method may inhibit enzyme
activity through a variety of mechanisms. By the way of example,
and without limitation, the inhibitors used in the methods
described herein may block the enzyme activity directly by acting
as a substrate for the enzyme.
[0045] The term "hydrido" denotes a single hydrogen atom (H). This
hydrido radical may be attached, for example, to an oxygen atom to
form a hydroxyl radical or two hydrido radicals may be attached to
a carbon atom to form a methylene (--CH2-) radical.
[0046] Where used, either alone or within other terms such as
"haloalkyl", "alkylsulfonyl", "alkoxyalkyl" and "hydroxyalkyl", the
term "alkyl" embraces linear, cyclic or branched radicals having
one to about twenty carbon atoms or, preferably, one to about
twelve carbon atoms. More preferred alkyl radicals are "lower
alkyl" radicals having one to about ten carbon atoms. Most
preferred are lower alkyl radicals having one to about six carbon
atoms. Examples of such radicals include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
iso-amyl, hexyl and the like.
[0047] The term "alkenyl" embraces linear or branched radicals
having at least one carbon-carbon double bond of two to about
twenty carbon atoms or, preferably, two to about twelve carbon
atoms. More preferred alkyl radicals are "lower alkenyl" radicals
having two to about six carbon atoms. Examples of alkenyl radicals
include ethenyl, propenyl, allyl, propenyl, butenyl and
4-methylbutenyl.
[0048] The term "alkynyl" denotes linear or branched radicals
having two to about twenty carbon atoms or, preferably, two to
about twelve carbon atoms. More preferred alkynyl radicals are
"lower alkynyl" radicals having two to about ten carbon atoms. Most
preferred are lower alkynyl radicals having two to about six carbon
atoms. Examples of such radicals include propargyl, butynyl, and
the like.
[0049] The terms "alkenyl", "lower alkenyl", embrace radicals
having "cis" and "trans" orientations, or alternatively, "E" and
"Z" orientations. The term "cycloalkyl" embraces saturated
carbocyclic radicals having three to twelve carbon atoms. More
preferred cycloalkyl radicals are "lower cycloalkyl" radicals
having three to about eight carbon atoms. Examples of such radicals
include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0050] The term "cycloalkenyl" embraces partially unsaturated
carbocyclic radicals having three to twelve carbon atoms. More
preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals
having four to about eight carbon atoms. Examples of such radicals
include cyclobutenyl, cyclopentenyl, cyclopentadienyl, and
cyclohexenyl.
[0051] The term "halo" means halogens such as fluorine, chlorine,
bromine or iodine.
[0052] The term "haloalkyl" embraces radicals wherein any one or
more of the alkyl carbon atoms is substituted with halo as defined
above. Specifically embraced are monohaloalkyl, dihaloalkyl and
polyhaloalkyl radicals. A monohaloalkyl radical, for one example,
may have either an iodo, bromo, chloro or fluoro atom within the
radical. Dihalo and polyhaloalkyl radicals may have two or more of
the same halo atoms or a combination of different halo radicals.
"Lower haloalkyl" embraces radicals having 1-6 carbon atoms.
Examples of haloalkyl radicals include fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and
dichloropropyl.
[0053] The term "hydroxyalkyl" embraces linear or branched alkyl
radicals having one to about ten carbon atoms any one of which may
be substituted with one or more hydroxyl radicals. More preferred
hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one
to six carbon atoms and one or more hydroxyl radicals. Examples of
such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,
hydroxybutyl and hydroxyhexyl.
[0054] The terms "alkoxy" and "alkyloxy" embrace linear or branched
oxy-containing radicals each having alkyl portions of one to about
ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy"
radicals having one to six carbon atoms. Examples of such radicals
include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
[0055] The term "alkoxyalkyl" embraces alkyl radicals having one or
more alkoxy radicals attached to the alkyl radical, that is, to
form monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy"
radicals may be further substituted with one or more halo atoms,
such as fluoro, chloro or bromo, to provide haloalkoxy radicals.
More preferred haloalkoxy radicals are "lower haloalkoxy" radicals
having one to six carbon atoms and one or more halo radicals.
Examples of such radicals include fluoromethoxy, chloromethoxy,
trifluoromethoxy, trifluoroethoxy, fluoroethoxy and
fluoropropoxy.
[0056] The term "aryl", alone or in combination, means a
carbocyclic aromatic system containing one, two or three rings
wherein such rings may be attached together in a pendent manner or
may be fused. The term "aryl" embraces aromatic radicals such as
phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl
moieties may also be substituted at a substitutable position with
one or more substituents selected independently from alkyl,
alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,
aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro,
alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and
aralkoxycarbonyl.
[0057] The term "heterocyclyl" embraces saturated, partially
unsaturated and unsaturated heteroatom-containing ring-shaped
radicals, where the heteroatoms may be selected from nitrogen,
sulfur and oxygen. Examples of saturated heterocyclyl radicals
include saturated 3 to 6-membered heteromonocylic group containing
1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl,
piperidino, piperazinyl, etc.); saturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially
unsaturated heterocyclyl radicals include dihydrothiophene,
dihydropyran, dihydrofuran and dihydrothiazole.
[0058] The term "heteroaryl" embraces unsaturated heterocyclyl
radicals. Examples of unsaturated heterocyclyl radicals, also
termed "heteroaryl" radicals include unsaturated 3 to 6 membered
heteromonocyclic group containing 1 to 4 nitrogen atoms, for
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.)
tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen
atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.),
etc.; unsaturated 3 to 6-membered heteromonocyclic group containing
an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to
6-membered heteromonocyclic group containing a sulfur atom, for
example, thienyl, etc.; unsaturated 3- to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl
(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,
etc.) etc.; unsaturated condensed heterocyclyl group containing 1
to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl,
benzoxadiazolyl, etc.); unsaturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.)
etc.; unsaturated condensed heterocyclyl group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl,
benzothiadiazolyl, etc.) and the like. The term also embraces
radicals where heterocyclyl radicals are fused with aryl radicals.
Examples of such fused bicyclic radicals include benzofuran,
benzothiophene, and the like. Said "heterocyclyl group" may have 1
to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino
and alkylamino.
[0059] The term "alkylthio" embraces radicals containing a linear
or branched alkyl radical, of one to about ten carbon atoms
attached to a divalent sulfur atom. More preferred alkylthio
radicals are "lower alkylthio" radicals having alkyl radicals of
one to six carbon atoms. Examples of such lower alkylthio radicals
are methylthio, ethylthio, propylthio, butylthio and hexylthio.
[0060] The term "alkylthioalkyl" embraces radicals containing an
alkylthio radical attached through the divalent sulfur atom to an
alkyl radical of one to about ten carbon atoms. More preferred
alkylthioalkyl radicals are "lower alkylthioalkyl" radicals having
alkyl radicals of one to six carbon atoms. Examples of such lower
alkylthioalkyl radicals include methylthiomethyl.
[0061] The term "alkylsulfinyl" embraces radicals containing a
linear or branched alkyl radical, of one to ten carbon atoms,
attached to a divalent --S(.dbd.O)-- radical. More preferred
alkylsulfinyl radicals are "lower alkylsulfinyl" radicals having
alkyl radicals of one to six carbon atoms. Examples of such lower
alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl,
butylsulfinyl and hexylsulfinyl.
[0062] The term "sulfonyl", whether used alone or linked to other
terms such as alkylsulfonyl, denotes respectively divalent radicals
--SO2--. "Alkylsulfonyl" embraces alkyl radicals attached to a
sulfonyl radical, where alkyl is defined as above. More preferred
alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having
one to six carbon atoms. Examples of such lower alkylsulfonyl
radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
The "alkylsulfonyl" radicals may be further substituted with one or
more halo atoms, such as fluoro, chloro or bromo, to provide
haloalkylsulfonyl radicals. The terms "sulfamyl", "aminosulfonyl"
and "sulfonamidyl" denote NH2O2S--.
[0063] The term "acyl" denotes a radical provided by the residue
after removal of hydroxyl from an organic acid. Examples of such
acyl radicals include alkanoyl and aroyl radicals. Examples of such
lower alkanoyl radicals include formyl, acetyl, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,
trifluoroacetyl.
[0064] The term "carbonyl", whether used alone or with other terms,
such as "alkoxycarbonyl", denotes --(C.dbd.O)--.
[0065] The term "aroyl" embraces aryl radicals with a carbonyl
radical as defined above. Examples of aroyl include benzoyl,
naphthoyl, and the like and the aryl in said aroyl may be
additionally substituted.
[0066] The terms "carboxy" or "carboxyl", whether used alone or
with other terms, such as "carboxyalkyl", denotes --CO2H.
[0067] The term "carboxyalkyl" embraces alkyl radicals substituted
with a carboxy radical. More preferred are "lower carboxyalkyl"
which embrace lower alkyl radicals as defined above, and may be
additionally substituted on the alkyl radical with halo. Examples
of such lower carboxyalkyl radicals include carboxymethyl,
carboxyethyl and carboxypropyl.
[0068] The term "alkoxycarbonyl" means a radical containing an
alkoxy radical, as defined above, attached via an oxygen atom to a
carbonyl radical. More preferred are "lower alkoxycarbonyl"
radicals with alkyl portions having 1 to 6 carbons. Examples of
such lower alkoxycarbonyl (ester) radicals include substituted or
unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
butoxycarbonyl and hexyloxycarbonyl.
[0069] The terms "alkylcarbonyl", "arylcarbonyl" and
"aralkylcarbonyl" include radicals having alkyl, aryl and aralkyl
radicals, as defined above, attached to a carbonyl radical.
Examples of such radicals include substituted or unsubstituted
methylcarbonyl, ethylcarbonyl, phenylcarbonyl and
benzylcarbonyl.
[0070] The term "aralkyl" embraces aryl-substituted alkyl radicals
such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and
diphenylethyl. The aryl in said aralkyl may be additionally
substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The terms benzyl and phenylmethyl are interchangeable.
[0071] The term "heterocyclylalkyl" embraces saturated and
partially unsaturated heterocyclyl-substituted alkyl radicals, such
as pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals,
such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl,
and quinolylethyl. The heteroaryl in said heteroaralkyl may be
additionally substituted with halo, alkyl, alkoxy, halkoalkyl and
haloalkoxy.
[0072] The term "aralkoxy" embraces aralkyl radicals attached
through an oxygen atom to other radicals.
[0073] The term "aralkoxyalkyl" embraces aralkoxy radicals attached
through an oxygen atom to an alkyl radical.
[0074] The term "aralkylthio" embraces aralkyl radicals attached to
a sulfur atom.
[0075] The term "aralkylthioalkyl" embraces aralkylthio radicals
attached through a sulfur atom to an alkyl radical.
[0076] The term "aminoalkyl" embraces alkyl radicals substituted
with one or more amino radicals. More preferred are "lower
aminoalkyl" radicals. Examples of such radicals include
aminomethyl, aminoethyl, and the like.
[0077] The term "alkylamino" denotes amino groups that have been
substituted with one or two alkyl radicals. Preferred are "lower
N-alkylamino" radicals having alkyl portions having 1 to 6 carbon
atoms. Suitable lower alkylamino may be mono or dialkylamino such
as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino
or the like.
[0078] The term "arylamino" denotes amino groups, which have been
substituted with one or two aryl radicals, such as N-phenylamino.
The "arylamino" radicals may be further substituted on the aryl
ring portion of the radical.
[0079] The term "aralkylamino" embraces aralkyl radicals attached
through an amino nitrogen atom to other radicals. The terms
"N-arylaminoalkyl" and "N-aryl-N-alkyl-aminoalkyl" denote amino
groups which have been substituted with one aryl radical or one
aryl and one alkyl radical, respectively, and having the amino
group attached to an alkyl radical. Examples of such radicals
include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl.
[0080] The term "aminocarbonyl" denotes an amide group of the
formula --C(.dbd.O)NH2.
[0081] The term "alkylaminocarbonyl" denotes an aminocarbonyl group
that has been substituted with one or two alkyl radicals on the
amino nitrogen atom. Preferred are "N-alkylaminocarbonyl"
"N,N-dialkylaminocarbonyl" radicals. More preferred are "lower
N-alkylaminocarbonyl" "lower N,N-dialkylaminocarbonyl" radicals
with lower alkyl portions as defined above.
[0082] The term "alkylaminoalkyl" embraces radicals having one or
more alkyl radicals attached to an aminoalkyl radical.
[0083] The term "aryloxyalkyl" embraces radicals having an aryl
radical attached to an alkyl radical through a divalent oxygen
atom.
[0084] The term "arylthioalkyl" embraces radicals having an aryl
radical attached to an alkyl radical through a divalent sulfur
atom.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0085] The present invention provides a combination therapy
comprising the administration to a subject of a therapeutically
effective amount of a COX-2 selective inhibitor in combination with
amyloid vaccination. The combination therapy is used to treat or
prevent Alzheimer's disease. When administered as part of a
combination therapy, the COX-2 selective inhibitor together with
the amyloid beta vaccine provides enhanced treatment options as
compared to administration of either the amyloid beta vaccine or
the COX-2 selective inhibitor alone.
[0086] Cox-2 Selective Inhibitors
[0087] Any cyclooxygenase-2 selective inhibitor or prodrug or
pharmaceutically acceptable salt thereof may be employed in the
composition of the current invention. In one embodiment, the
cyclooxygenase-2 selective inhibitor can be, for example, the
cyclooxygenase-2 selective inhibitor meloxicam, Formula B-1 (CAS
registry number 71125-38-7) or a pharmaceutically acceptable salt
or prodrug thereof. 3
[0088] In yet another embodiment, the cyclooxygenase-2 selective
inhibitor is the cyclooxygenase-2 selective inhibitor,
6-[[5-(4-chlorobenzoyl)-1,4--
dimethyl-1H-pyrrol-2-yl]methyl]-3(2H)-pyridazinone, Formula B-2
(CAS registry number 179382-91-3) or a pharmaceutically acceptable
salt or prodrug thereof. 4
[0089] In a preferred embodiment the cyclooxygenase-2 selective
inhibitor is preferably of the chromene structural class that is a
substituted benzopyran or a substituted benzopyran analog, and even
more preferably selected from the group consisting of substituted
benzothiopyrans, dihydroquinolines, or dihydronaphthalenes having
the general Formula I shown below and possessing, by way of example
and not limitation, the structures disclosed in Table 1, including
the diastereomers, enantiomers, racemates, tautomers, salts,
esters, amides and prodrugs thereof. Furthermore, benzopyran
cyclooxygenase-2 selective inhibitors useful in the practice of the
present methods are described in U.S. Pat. Nos. 6,034,256 and
6,077,850 herein incorporated by reference in their entirety.
[0090] In one embodiment, the cyclooxygenase-2 selective inhibitor
is of the chromene structural class and is represented by Formula
I: 5
[0091] or an isomer, a pharmaceutically acceptable salt, ester, or
prodrug thereof;
[0092] wherein n is an integer which is 0, 1, 2, 3 or 4;
[0093] wherein G is O, S or NR.sup.a;
[0094] wherein R.sup.a is alkyl;
[0095] wherein R.sup.1 is selected from the group consisting of H
and aryl;
[0096] wherein R.sup.2 is selected from the group consisting of
carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and
alkoxycarbonyl;
[0097] wherein R.sup.3 is selected from the group consisting of
haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally
substituted with one or more radicals selected from alkylthio,
nitro and alkylsulfonyl; and
[0098] wherein each R.sup.4 is independently selected from the
group consisting of H, halo, alkyl, aralkyl, alkoxy, aryloxy,
heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy,
alkylamino, arylamino, aralkylamino, heteroarylamino,
heteroarylalkylamino, nitro, amino, aminosulfonyl,
alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,
aralkylaminosulfonyl, heteroaralkylaminosulfonyl- ,
heterocyclosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl,
optionally substituted aryl, optionally substituted heteroaryl,
aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl,
and alkylcarbonyl;
[0099] or wherein R.sup.4 together with the carbon atoms to which
it is attached and the remainder of ring E forms a naphthyl
radical.
[0100] The cyclooxygenase-2 selective inhibitor may also be a
compound of Formula (I) or an isomer, a pharmaceutically acceptable
salt, ester, or prodrug thereof wherein:
[0101] n is an integer which is 0, 1, 2, 3 or 4;
[0102] G is O, S or NR.sup.b;
[0103] R.sup.1 is H;
[0104] R.sup.b is alkyl;
[0105] R.sup.2 is selected from the group consisting of carboxyl,
aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
[0106] R.sup.3 is selected from the group consisting of haloalkyl,
alkyl, aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl,
aralkyl, cycloalkyl, and aryl each is independently optionally
substituted with one or more radicals selected from the group
consisting of alkylthio, nitro and alkylsulfonyl; and
[0107] each R.sup.4 is independently selected from the group
consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy,
heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy,
alkylamino, arylamino, aralkylamino, heteroarylamino,
heteroarylalkylamino, nitro, amino, aminosulfonyl,
alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,
aralkylaminosulfonyl, heteroaralkylaminosulfonyl- ,
heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl,
optionally substituted heteroaryl, aralkylcarbonyl,
heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl;
or wherein R.sup.4 together with ring E forms a naphthyl
radical.
[0108] In a further embodiment, the cyclooxygenase-2 selective
inhibitor may also be a compound of Formula (I), or an isomer, a
pharmaceutically acceptable salt, ester, or prodrug thereof;
wherein:
[0109] n is an integer which is 0, 1, 2, 3 or 4;
[0110] G is oxygen or sulfur;
[0111] R.sup.1 is H;
[0112] R.sup.2 is carboxyl, lower alkyl, lower aralkyl or lower
alkoxycarbonyl;
[0113] R.sup.3 is lower haloalkyl, lower cycloalkyl or phenyl;
and
[0114] each R.sup.4 is H, halo, lower alkyl, lower alkoxy, lower
haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino,
aminosulfonyl, lower alkylaminosulfonyl, 5-membered
heteroarylalkylaminosulfonyl, 6-membered
heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl,
5-membered nitrogen-containing heterocyclosulfonyl,
6-membered-nitrogen containing heterocyclosulfonyl, lower
alkylsulfonyl, optionally substituted phenyl, lower
aralkylcarbonyl, or lower alkylcarbonyl; or
[0115] wherein R.sup.4 together with the carbon atoms to which it
is attached and the remainder of ring E forms a naphthyl
radical.
[0116] The cyclooxygenase-2 selective inhibitor may also be a
compound of Formula (I) or an isomer, a pharmaceutically acceptable
salt, ester, or prodrug thereof; wherein:
[0117] R.sup.2 is carboxyl;
[0118] R.sup.3 is lower haloalkyl; and
[0119] each R.sup.4 is H, halo, lower alkyl, lower haloalkyl, lower
haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower
alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl,
6-membered heteroarylalkylaminosulfonyl, lower
aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered
nitrogen-containing heterocyclosulfonyl, optionally substituted
phenyl, lower aralkylcarbonyl, or lower alkylcarbonyl; or wherein
R.sup.4 together with ring E forms a naphthyl radical.
[0120] The cyclooxygenase-2 selective inhibitor may also be a
compound of Formula (I) or an isomer, a pharmaceutically acceptable
salt, ester, or prodrug thereof; wherein:
[0121] n is an integer which is 0, 1, 2, 3 or 4;
[0122] R.sup.3 is fluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
difluoromethyl, or trifluoromethyl; and
[0123] each R.sup.4 is H, chloro, fluoro, bromo, iodo, methyl,
ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl,
methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl,
difluoromethyl, trifluoromethoxy, amino, N,N-dimethylamino,
N,N-diethylamino, N-phenylmethylaminosulfonyl,
N-phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, nitro,
N,N-dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl,
N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl,
N,N-dimethylaminosulfonyl, N-(2-methylpropyl)aminosulfonyl,
N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl,
2,2-dimethylpropylcarbonyl, phenylacetyl or phenyl; or wherein
R.sup.4 together with the carbon atoms to which it is attached and
the remainder of ring E forms a naphthyl radical.
[0124] The cyclooxygenase-2 selective inhibitor may also be a
compound of Formula (I) or an isomer, a pharmaceutically acceptable
salt, ester, or prodrug thereof; wherein:
[0125] n is an integer which is 0, 1, 2, 3 or 4;
[0126] R.sup.3 is trifluoromethyl or pentafluoroethyl; and
[0127] each R.sup.4 is independently H, chloro, fluoro, bromo,
iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy,
trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl,
N-phenylethylaminosulfonyl- , N-(2-furylmethyl)aminosulfonyl,
N,N-dimethylaminosulfonyl, N-methylaminosulfonyl,
N-(2,2-dimethylethyl)aminosulfonyl, dimethylaminosulfonyl,
2-methylpropylaminosulfonyl, N-morpholinosulfonyl, methylsulfonyl,
benzylcarbonyl, or phenyl; or wherein R.sup.4 together with the
carbon atoms to which it is attached and the remainder of ring E
forms a naphthyl radical.
[0128] In yet another embodiment, the cyclooxygenase-2 selective
inhibitor used in connection with the method(s) of the present
invention can also be a compound having the structure of Formula
(I) or an isomer, a pharmaceutically acceptable salt, ester, or
prodrug thereof:
[0129] wherein:
[0130] n=4;
[0131] G is O or S;
[0132] R.sup.1 is H;
[0133] R.sup.2 is CO.sub.2H;
[0134] R.sup.3 is lower haloalkyl;
[0135] a first R.sup.4 corresponding to R.sup.9 is hydrido or
halo;
[0136] a second R.sup.4 corresponding to R.sup.10 is H, halo, lower
alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower
dialkylaminosulfonyl, lower alkylaminosulfonyl, lower
aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5-membered
nitrogen-containing heterocyclosulfonyl, or 6-membered
nitrogen-containing heterocyclosulfonyl;
[0137] a third R.sup.4 corresponding to R" is H, lower alkyl, halo,
lower alkoxy, or aryl; and
[0138] a fourth R.sup.4 corresponding to R.sup.12 is H, halo, lower
alkyl, lower alkoxy, and aryl;
[0139] wherein Formula (I) is represented by Formula (Ia): 6
[0140] or an isomer, a pharmaceutically acceptable salt, ester, or
prodrug thereof.
[0141] The cyclooxygenase-2 selective inhibitor used in connection
with the method(s) of the present invention can also be a compound
of having the structure of Formula (Ia) or an isomer, a
pharmaceutically acceptable salt, ester, or prodrug thereof;
wherein:
[0142] R.sup.8 is trifluoromethyl or pentafluoroethyl;
[0143] R.sup.9 is H, chloro, or fluoro;
[0144] R.sup.10 is H, chloro, bromo, fluoro, iodo, methyl,
tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl,
dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl,
benzylaminosulfonyl, phenylethylaminosulfonyl,
methylpropylaminosulfonyl, methylsulfonyl, or
morpholinosulfonyl;
[0145] R.sup.11 is H, methyl, ethyl, isopropyl, tert-butyl, chloro,
methoxy, diethylamino, or phenyl; and
[0146] R.sup.12 is H, chloro, bromo, fluoro, methyl, ethyl,
tert-butyl, methoxy, or phenyl.
[0147] Examples of exemplary chromene cyclooxygenase-2 selective
inhibitors are depicted in Table 1 below.
1TABLE 1 Examples of Chromene Cyclooxygenase-2 Selective Inhibitors
as Embodiments Compound Number Structural Formula B-3 7
6-Nitro-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid B-4 8
6-Chloro-8-methyl-2-trifluoromethyl- 2H-1-benzopyran-3-carboxylic
acid B-5 9 ((S)-6-Chloro-7-(1,1-dimethylethyl)-2-
(trifluoromethyl-2H-1-benz- opyran-3-carboxylic acid B-6 10
2-Trifluoromethyl-2H-naphtho[2,3-b] pyran-3-carboxylic acid B-7 11
6-Chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)- -2H-1-
benzopyran-3-carboxylic acid B-8 12
((S)-6,8-Dichloro-2-(trifluoromethyl)- 2H-1-benzopyran-3-carboxy-
lic acid B-9 13 6-Chloro-2-(trifluoromethyl)-4-ph- enyl-2H-
1-benzopyran-3-carboxylic acid B-10 14
6-(4-Hydroxybenzoyl)-2-(trifluoromethyl)-
2H-1-benzopyran-3-carboxylic acid B-11 15
2-(Trifluoromethyl)-6-[(trifluoromethyl)thio]-
2H-1-benzothiopyran-3-carboxylic acid B-12 16
6,8-Dichloro-2-trifluoromethyl-2H-1- benzothiopyran-3-carboxylic
acid B-13 17 6-(1,1-Dimethylethyl)-2-(trifluorome- thyl)-
2H-1-benzothiopyran-3-carboxylic acid B-14 18
6,7-Difluoro-1,2-dihydro-2-(trifluoromethyl)- 3-quinolinecarboxylic
acid B-15 19 6-Chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-
3-quinolinecarboxylic acid B-16 20
6-Chloro-2-(trifluoromethyl)-1,2-dihydro [1,8]naphthyridine-3-car-
boxylic acid B-17 21 ((S)-6-Chloro-1,2-dihydro-2-(-
trifluoromethyl)- 3-quinolinecarboxylic acid
[0148] In a further preferred embodiment, the cyclooxygenase
inhibitor is selected from the class of tricyclic cyclooxygenase-2
selective inhibitors represented by the general structure of
Formula II: 22
[0149] wherein A is selected from the group consisting of partially
unsaturated or unsaturated heterocyclyl and partially unsaturated
or unsaturated carbocyclic rings;
[0150] wherein R.sup.1 is selected from the group consisting of
heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R.sup.1 is
optionally substituted at a substitutable position with one or more
radicals selected from alkyl, haloalkyl, cyano, carboxyl,
alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,
alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo,
alkoxy and alkylthio;
[0151] wherein R.sup.2 is selected from the group consisting of
methyl or amino; and
[0152] wherein R.sup.3 is selected from the group consisting of a
radical selected from H, halo, alkyl, alkenyl, alkynyl, oxo, cyano,
carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio,
alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl,
cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl,
hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl,
aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl,
aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl,
alkylaminocarbonyl, N-arylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl,
alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,
N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,
N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl; or
a pharmaceutically acceptable salt thereof.
[0153] In a still more preferred embodiment of the invention the
cyclooxygenase-2 selective inhibitor represented by the above
Formula II is selected from the group of compounds, illustrated in
Table 2, consisting of celecoxib (B-18; U.S. Pat. No. 5,466,823;
CAS No. 169590-42-5), valdecoxib (B-19; U.S. Pat. No. 5,633,272;
CAS No. 181695-72-7), deracoxib (B-20; U.S. Pat. No. 5,521,207; CAS
No. 169590-41-4), rofecoxib (B-21; CAS No. 162011-90-7), etoricoxib
(MK-663; B-22; PCT publication WO 98/03484), JTE-522 (B-23), or an
isomer, ester, a pharmaceutically acceptable salt or prodrug
thereof.
2TABLE 2 Examples of Tricyclic Cyclooxygenase-2 Selective
Inhibitors as Embodiments Compound Number Structural Formula B-18
23 B-19 24 B-20 25 B-21 26 B-22 27 B-23 28
[0154] In an even more preferred embodiment, the cyclooxygenase-2
selective inhibitor is selected from the group consisting of
celecoxib, rofecoxib and etoricoxib.
[0155] In another highly preferred embodiment of the invention,
parecoxib (B-24, U.S. Pat. No. 5,932,598, CAS No. 198470-84-7),
which is a therapeutically effective prodrug of the tricyclic
cyclooxygenase-2 selective inhibitor valdecoxib, B-19, may be
advantageously employed as a source of a cyclooxygenase inhibitor
(U.S. Pat. No. 5,932,598, herein incorporated by reference). 29
[0156] A preferred form of parecoxib is sodium parecoxib.
[0157] In another preferred embodiment of the invention, the
compound having the formula B-25 that has been previously described
in International Publication number WO 00/24719 (which is herein
incorporated by reference), is another tricyclic cyclooxygenase-2
selective inhibitor which may be advantageously employed. 30
[0158] Another preferred cyclooxygenase-2 selective inhibitor that
is useful in connection with the method(s) of the present invention
is N-(2-cyclohexyloxynitrophenyl)-methane sulfonamide (NS-398)
having a structure shown below as B-26. 31
[0159] In yet a further preferred embodiment of the invention, the
cyclooxygenase inhibitor used in connection with the method(s) of
the present invention can be selected from the class of
phenylacetic acid derivative cyclooxygenase-2 selective inhibitors
represented by the general structure of Formula (III): 32
[0160] or an isomer, a pharmaceutically acceptable salt, ester, or
prodrug thereof;
[0161] wherein
[0162] R.sup.16 is methyl or ethyl;
[0163] R.sup.17 is chloro or fluoro;
[0164] R.sup.18 is hydrogen or fluoro;
[0165] R.sup.19 is hydrogen, fluoro, chloro, methyl, ethyl,
methoxy, ethoxy or hydroxy;
[0166] R.sup.20 is hydrogen or fluoro; and
[0167] R.sup.21 is chloro, fluoro, trifluoromethyl or methyl,
provided that R.sup.17, R.sup.18, R.sup.19 and R.sup.20 are not all
fluoro when R.sup.16 is ethyl and R.sup.19 is H.
[0168] A particularly preferred phenylacetic acid derivative
cyclooxygenase-2 selective inhibitor used in connection with the
method(s) of the present invention is a compound that has the
designation of COX 189 (B-211) and that has the structure shown in
Formula (III) or an isomer, a pharmaceutically acceptable salt,
ester, or prodrug thereof, wherein:
[0169] R.sup.16 is ethyl;
[0170] R.sup.17 and R.sup.19 are chloro;
[0171] R.sup.18 and R.sup.20 are hydrogen; and and R.sup.21 is
methyl.
[0172] In yet another embodiment, the cyclooxygenase-2 selective
inhibitor is represented by Formula (IV): 33
[0173] or an isomer, a pharmaceutically acceptable salt, an ester,
or a prodrug thereof,
[0174] wherein:
[0175] X is O or S;
[0176] J is a carbocycle or a heterocycle;
[0177] R.sup.22 is NHSO.sub.2CH.sub.3 or F;
[0178] R.sup.23 is H, NO.sub.2, or F; and
[0179] R.sup.24 is H, NHSO.sub.2CH.sub.3, or
(SO.sub.2CH.sub.3)C.sub.6H.su- b.4.
[0180] According to another embodiment, the cyclooxygenase-2
selective inhibitors used in the present method(s) have the
structural Formula (V): 34
[0181] or an isomer, a pharmaceutically acceptable salt, an ester,
or a prodrug thereof, wherein:
[0182] T and M independently are phenyl, naphthyl, a radical
derived from a heterocycle comprising 5 to 6 members and possessing
from 1 to 4 heteroatoms, or a radical derived from a saturated
hydrocarbon ring having from 3 to 7 carbon atoms;
[0183] Q.sup.1, Q.sup.2, L.sup.1 or L.sup.2 are independently
hydrogen, halogen, lower alkyl having from 1 to 6 carbon atoms,
trifluoromethyl, or lower methoxy having from 1 to 6 carbon atoms;
and
[0184] at least one of Q.sup.1, Q.sup.2, L.sup.1 or L.sup.2 is in
the para position and is --S(O).sub.n--R, wherein n is 0, 1, or 2
and R is a lower alkyl radical having 1 to 6 carbon atoms or a
lower haloalkyl radical having from 1 to 6 carbon atoms, or an
--SO.sub.2NH.sub.2; or,
[0185] Q.sup.1 and Q.sup.2 are methylenedioxy; or
[0186] L.sup.1 and L.sup.2 are methylenedioxy; and
[0187] R.sup.25, R.sup.26, R.sup.27, and R.sup.28 are independently
hydrogen, halogen, lower alkyl radical having from 1 to 6 carbon
atoms, lower haloalkyl radical having from 1 to 6 carbon atoms, or
an aromatic radical selected from the group consisting of phenyl,
naphthyl, thienyl, furyl and pyridyl; or,
[0188] R.sup.25 and R.sup.26 are 0; or,
[0189] R.sup.27 and R.sup.28 are 0; or,
[0190] R.sup.25, R.sup.26, together with the carbon atom to which
they are attached, form a saturated hydrocarbon ring having from 3
to 7 carbon atoms; or,
[0191] R.sup.27, R.sup.28, together with the carbon atom to which
they are attached, form a saturated hydrocarbon ring having from 3
to 7 carbon atoms.
[0192] In a particularly preferred embodiment, the compounds
N-(2-cyclohexyloxynitrophenyl)methane sulfonamide, and
(E)-4-[(4-methylphenyl)(tetrahydro-2-oxo-3-furanylidene)
methyl]benzenesulfonamide having the structure of Formula (V) are
employed as cyclooxygenase-2 selective inhibitors.
[0193] Exemplary compounds that are useful for the cyclooxygenase-2
selective inhibitor in connection with the method(s) of the present
invention, the structures for which are set forth in Table 3 below,
include, but are not limited to:
[0194] 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid
(B-27);
[0195]
6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-28);
[0196]
8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-29);
[0197]
6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carb-
oxylic acid (B-30);
[0198] 2-trifluoromethyl-3H-naphtho[2,1-b]pyran-3-carboxylic acid
(B-31);
[0199]
7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxyli-
c acid (B-32);
[0200] 6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid
(B-33);
[0201] 8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid
(B-34);
[0202]
6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-35);
[0203] 5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-36);
[0204] 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid
(B-37);
[0205] 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-38);
[0206]
6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxyl-
ic acid (B-39);
[0207]
7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-40);
[0208] 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid
(B-41);
[0209]
6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-42);
[0210]
6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-43);
[0211]
6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-44);
[0212] 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-45);
[0213] 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-46);
[0214]
6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-47);
[0215]
8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-48)
[0216]
8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-49);
[0217]
6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-50);
[0218]
8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-51);
[0219]
8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-52);
[0220]
8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-53);
[0221]
6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-54);
[0222]
6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-55);
[0223]
6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-
-3-carboxylic acid (B-56);
[0224]
6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-car-
boxylic acid (B-57);
[0225]
6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carbo-
xylic acid (B-58);
[0226]
6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carb-
oxylic acid (B-59);
[0227]
6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopy-
ran-3-carboxylic acid (B-60);
[0228]
6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-
-3-carboxylic acid (B-61);
[0229]
6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-62);
[0230]
8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-b-
enzopyran-3-carboxylic acid (B-63);
[0231]
6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid
(B-64);
[0232] 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-65);
[0233]
8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxyli-
c acid (B-66);
[0234]
6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-67);
[0235]
6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-68);
[0236]
6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopy-
ran-3-carboxylic acid (B-69);
[0237]
6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopy-
ran-3-carboxylic acid (B-70);
[0238] 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid
(B-71);
[0239]
7-(1,1-dimethylethyl)-2-pentafluoroethyl-2H-1-benzopyran-3-carboxyl-
ic acid (B-72);
[0240] 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic
acid (B-73);
[0241]
3-[(3-Chloro-phenyl)-(4-methanesulfonyl-phenyl)-methylene]-dihydro--
furan-2-one or BMS-347070 (B-74);
[0242]
8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl)phenyl-imidazo(1,2--
a)pyridine (B-75);
[0243]
5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2-(5H)-furanone
(B-76);
[0244]
5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-
pyrazole (B-77);
[0245]
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1-phenyl-3-(trifluo-
romethyl)pyrazole (B-78);
[0246]
4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesu-
lfonamide (B-79);
[0247]
4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide
(B-80);
[0248]
4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfonamide
(B-81);
[0249]
4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide
(B-82);
[0250]
4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-yl)benzenesul-
fonamide (B-83);
[0251]
4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulf-
onamide (B-84);
[0252]
4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl)benzen-
esulfonamide (B-85);
[0253] 4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)benzenesulfonamide
(B-86);
[0254]
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide (B-87);
[0255]
4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(B-88);
[0256]
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide (B-89);
[0257]
4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenes-
ulfonamide (B-90);
[0258]
4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide (B-91);
[0259]
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide (B-92);
[0260]
4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide (B-93);
[0261]
4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesul-
fonamide (B-94);
[0262]
4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide
(B-95);
[0263]
4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide (B-96);
[0264]
4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide
(B-97);
[0265]
4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]-
benzenesulfonamide (B-98);
[0266]
4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-
]benzenesulfonamide (B-99);
[0267] 4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide
(B-100);
[0268]
4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl]benzenesulf-
onamide (B-101);
[0269]
4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide (B-102);
[0270]
5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene
(B-103);
[0271]
4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide
(B-104);
[0272]
6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[3.4]oct-6-ene
(B-105);
[0273]
5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]-
hept-5-ene (B-106);
[0274]
4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl]benzenesulf-
onamide (B-107);
[0275]
5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[-
2.4]hept-5-ene (B-108);
[0276]
5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]h-
ept-5-ene (B-109);
[0277]
4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamid-
e (B-110);
[0278]
2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylp-
henyl)thiazole (B-111);
[0279]
2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thi-
azole (B-112);
[0280]
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole
(B-113);
[0281]
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethylthia-
zole (B-114);
[0282]
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole
(B-115);
[0283]
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole
(B-116);
[0284]
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino)thia-
zole (B-117);
[0285]
2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-(methylsulf-
onyl)phenyl]thiazole (B-118);
[0286]
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethylthia-
zole (B-119);
[0287]
1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-d-
ien-3-yl]benzene (B-120);
[0288]
4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-dien-3-yl]benzenes-
ulfonamide (B-121);
[0289]
5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6--
diene (B-122);
[0290]
4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl]benzenesulfonami-
de (B-123);
[0291]
6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)phenyl]-pyridine--
3-carbonitrile (B-124);
[0292]
2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyridine-3--
carbonitrile (B-125);
[0293]
6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyl-pyridine-3-
-carbonitrile (B-126);
[0294]
4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide (B-127);
[0295]
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide (B-128);
[0296]
4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide (B-129);
[0297]
3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-y-
l]pyridine (B-130);
[0298]
2-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl-
]pyridine (B-131);
[0299]
2-methyl-4-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imid-
azol-2-yl]pyridine (B-132);
[0300]
2-methyl-6-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imid-
azol-2-yl]pyridine (B-133);
[0301]
4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide (B-134);
[0302]
2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromet-
hyl)-1H-imidazole (B-135);
[0303]
4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenes-
ulfonamide (B-136);
[0304]
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1H-imidazo-
le (B-137);
[0305]
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1H-imidazo-
le (B-138);
[0306]
2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]--
1H-imidazole (B-139);
[0307]
2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-4-(trifluo-
romethyl)-1H-imidazole (B-140);
[0308]
1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazol-
e (B-141);
[0309]
2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1-
H-imidazole (B-142);
[0310]
4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl-
]benzenesulfonamide (B-143);
[0311]
2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluo-
romethyl)-1H-imidazole (B-144);
[0312]
4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl-
]benzenesulfonamide (B-145);
[0313]
2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1-
H-imidazole (B-146);
[0314]
4-[2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide (B-147);
[0315]
1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-1-
H-imidazole (B-148);
[0316]
4-[2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide (B-149);
[0317]
4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide
(B-150);
[0318]
4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]-
benzenesulfonamide (B-151);
[0319]
1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluor-
omethyl)-1H-pyrazole (B-152);
[0320]
4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]b-
enzenesulfonamide (B-153);
[0321]
N-phenyl-[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(triflu-
oromethyl)-1H-pyrazol-1-yl]acetamide (B-154);
[0322] ethyl
[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoro-
methyl)-1H-pyrazol-1-yl]acetate (B-155);
[0323]
4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-1-
H-pyrazole (B-156);
[0324]
4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-5-
-(trifluoromethyl)pyrazole (B-157);
[0325]
1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluor-
omethyl)-1H-pyrazole (B-158);
[0326]
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H--
imidazole (B-159);
[0327]
4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1-
H-imidazole (B-160);
[0328]
5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(triflu-
oromethyl)pyridine (B-161);
[0329]
2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluo-
romethyl)pyridine (B-162);
[0330]
5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-
-(trifluoromethyl)pyridine (B-163);
[0331]
2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluor-
omethyl)pyridine (B-164);
[0332]
4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonami-
de (B-165);
[0333] 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene
(B-166);
[0334]
5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole
(B-167);
[0335] 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide
(B-168);
[0336] 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide
(B-169);
[0337] 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide
(B-170);
[0338] 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide
(B-171);
[0339]
1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene
(B-172);
[0340]
1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)b-
enzene (B-173);
[0341]
1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene
(B-174);
[0342]
1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzen-
e (B-175);
[0343]
1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)b-
enzene (B-176);
[0344]
1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzen-
e (B-177);
[0345]
1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfon-
yl)benzene (B-178);
[0346]
4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonami-
de (B-179);
[0347]
1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfon-
yl)benzene (B-180);
[0348]
4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonami-
de (B-181);
[0349] 4-[2-(4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide
(B-182);
[0350] 4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide
(B-183);
[0351]
1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene
(B-184);
[0352]
1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzen-
e (B-185);
[0353]
4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl]benzenesulfonamide
(B-186);
[0354]
1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)-
benzene (B-187);
[0355]
4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide
(B-188);
[0356]
4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]benzenesulfonamide
(B-189);
[0357] ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)
phenyl]oxazol-2-yl]-2-benzyl-acetate (B-190);
[0358]
2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]aceti-
c acid (B-191);
[0359]
2-(tert-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazo-
le (B-192);
[0360]
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole
(B-193);
[0361]
4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole
(B-194);
[0362]
4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzen-
esulfonamide (B-195);
[0363]
6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3--
carboxylic acid (B-196);
[0364]
6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid (B-197);
[0365]
5,5-dimethyl-3-(3-fluorophenyl)-4-methylsulfonyl-2(5H)-furanone
(B-198);
[0366] 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic
acid (B-199);
[0367]
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide (B-200);
[0368]
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesu-
lfonamide (B-201);
[0369]
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide (B-202);
[0370]
3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]-
pyridine (B-203);
[0371]
2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imida-
zol-2-yl]pyridine (B-204);
[0372]
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide (B-205);
[0373] 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide
(B-206);
[0374] 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide
(B-207);
[0375]
[2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzenesulfona-
mide (B-208);
[0376] 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide
(B-209);
[0377]
4-[5-(2-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzen-
esulfonamide (B-210);
[0378] [2-(2-chloro-6-fluoro-phenylamino)-5-methyl-phenyl]-acetic
acid or COX 189 (B-211);
[0379] N-(4-Nitro-2-phenoxy-phenyl)-methanesulfonamide or
nimesulide (B-212);
[0380]
N-[6-(2,4-difluoro-phenoxy)-1-oxo-indan-5-yl]-methanesulfonamide or
flosulide (B-213);
[0381]
N-[6-(2,4-Difluoro-phenylsulfanyl)-1-oxo-1H-inden-5-yl]-methanesulf-
onamide, soldium salt or L-745337 (B-214);
[0382]
N-[5-(4-fluoro-phenylsulfanyl)-thiophen-2-yl]-methanesulfonamide or
RWJ-63556 (B-215);
[0383]
3-(3,4-Difluoro-phenoxy)-4-(4-methanesulfonyl-phenyl)-5-methyl-5-(2-
,2,2-trifluoroethyl)-5H-furan-2-one or L-784512 or L-784512
(B-216);
[0384]
(5Z)-2-amino-5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyle-
ne]-4(5H)-thiazolone or darbufelone (B-217);
[0385] CS-502 (B-218);
[0386] LAS-34475 (B-219);
[0387] LAS-34555 (B-220);
[0388] S-33516 (B-221);
[0389] SD-8381 (B-222);
[0390] L-783003 (B-223);
[0391]
N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesul-
fonamide or
[0392] T-614 (B-224);
[0393] D-1367 (B-225);
[0394] L-748731 (B-226);
[0395]
(6aR,10aR)-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy--
6,6-dimethyl-6H-dibenzo[b,d]pyran-9-carboxylic acid or CT3
(B-227);
[0396] CGP-28238 (B-228);
[0397]
4-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]dihydro-2--
methyl-2H-1,2-oxazin-3(4H)-one or BF-389 (B-229);
[0398] GR-253035 (B-230);
[0399] 6-dioxo-9H-purin-8-yl-cinnamic acid (B-231);
[0400] S-2474 (B-232);
[0401] 4-[4-(methyl)-sulfonyl)phenyl]-3-phenyl-2(5H)-furanone;
[0402] 4-(5-methyl-3-phenyl-4-isoxazolyl);
[0403]
2-(6-methylpyrid-3-yl)-3-(4-methylsulfonylphenyl)-5-chloropyridine;
[0404]
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl];
[0405] N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl];
[0406]
4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1-yl]b-
enzenesulfonamide;
[0407]
(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic
acid;
[0408]
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridzainone;
[0409] 2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic
acid;
[0410]
6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3--
carboxylic acid;
[0411]
[2-(2,4-dichloro-6-ethyl-3,5-dimethyl-phenylamino)-5-propyl-phenyl]-
-acetic acid;
[0412] or an isomer, a pharmaceutically acceptable salt, ester or
prodrug thereof.
3TABLE 3 Examples of Cyclooxygenase-2 Selective Inhibitors as
Embodiments Compound Number Structural Formula B-26 35
N-(2-cyclohexyloxynitroph- enyl) methane sulfonamide or NS-398;
B-27 36 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic
acid; B-28 37 6-chloro-7-methyl-2-trifluoromethyl-2H-1--
benzopyran- 3-carboxylic acid; B-29 38
8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran- 3-carboxylic
acid; B-30 39 6-chloro-8-(1-methylethyl)-2-triflu- oromethyl-
2H-1-benzopyran-3-carboxylic acid; B-31 40
2-trifluoromethyl-3H-naphtho[2,1-b]pyran-3- carboxylic acid; B-32
41 7-(1,1-dimethylethyl)-2-trifluorome- thyl-2H-1-
benzopyran-3-carboxylic acid; B-33 42
6-bromo-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid; B-34
43 8-chloro-2-trifluoromethyl-2H-1-ben- zopyran-3- carboxylic acid;
B-35 44 6-trifluoromethoxy-2-trifluoromethyl-2H-1-
benzopyran-3-carboxylic acid; B-36 45
5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid;
B-37 46 8-phenyl-2-trifluoromethyl-2H-1-ben- zopyran-3- carboxylic
acid; B-38 47 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-
3-carboxylic acid; B-39 48 6,8-bis(dimethylethyl)-2-trifluorom-
ethyl-2H-1- benzopyran-3-carboxylic acid; B-40 49
7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran- 3-carboxylic
acid; B-41 50 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-
carboxylic acid; B-42 51
6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benz- opyran- 3-carboxylic
acid; B-43 52 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-
3-carboxylic acid; B-44 53 6-chloro-7-phenyl-2-trifluoromethyl-
-2H-1-benzopyran- 3-carboxylic acid; B-45 54
6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid;
B-46 55 6,8-dichloro-2-trifluoromethyl-2H-1- -benzopyran-3-
carboxylic acid; B-47 56
6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran- 3-carboxylic
acid; B-48 57 8-chloro-6-methyl-2-trifluoromethyl-
-2H-1-benzopyran- 3-carboxylic acid; B-49 58
8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran- 3-carboxylic
acid; B-50 59 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-
carboxylic acid; B-51 60 8-bromo-6-fluoro-2-trifluoromethyl--
2H-1-benzopyran-3- carboxylic acid; B-52 61
8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic
acid; B-53 62 8-bromo-5-fluoro-2-trifluoromethyl--
2H-1-benzopyran-3- carboxylic acid; B-54 63
6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran- 3-carboxylic
acid; B-55 64
6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic
acid; B-56 65 6-[[(phenylmethyl)amino]sulfonyl]-2-
-trifluoromethyl- 2H-1-benzopyran-3-carboxylic acid; B-57 66
6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-
benzopyran-3-carboxylic acid; B-58 67
6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-
benzopyran-3-carboxylic acid; B-59 68
6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-
benzopyran-3-carboxylic acid; B-60 69
6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-
2H-1-benzopyran-3-carboxylic acid; B-61 70
6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-
2H-1-benzopyran-3-carboxylic acid; B-62 71
6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic
acid; B-63 72 8-chloro-6-[[(phenylmethyl)amino]su- lfonyl]-2-
trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; B-64 73
6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyr- an-3- carboxylic
acid; B-65 74 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-
carboxylic acid; B-66 75 8-chloro-5,6-dimethyl-2-trifluoromethyl-2-
H-1- benzopyran-3-carboxylic acid, B-67 76
6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran- 3-carboxylic
acid; B-68 77 6-benzylsulfonyl-2-trifluoromethyl-- 2H-1-benzopyran-
3-carboxylic acid; B-69 78
6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-
2H-1-benzopyran-3-carboxylic acid; B-70 79
6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-
2H-1-benzopyran-3-carboxylic acid; B-71 80
6-iodo-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid; B-72
81 7-(1,1-dimethylethyl)-2-pentafluoroethyl-2H-1-- benzopyran-
3-carboxylic acid; B-73 82
6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3- carboxylic acid;
B-74 83 3-[(3-chloro-phenyl)-(4-methanesulf- onyl-phenyl)-
methylene]-dihydro-furan-2-one or BMS-347070; B-75 84
8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl)- phenyl-
imidazo(1,2-a)pyridine; B-76 85
5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2- (5H)-furanone;
B-77 86 5-(4-fluorophenyl)-1-[4-(m- ethylsulfonyl)phenyl]-3-
(trifluoromethyl)pyrazole; B-78 87
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
1-phenyl-3-(trifluoromethyl)pyrazole; B-79 88
4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-
1-yl)benzenesulfonamide; B-80 89
4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl) benzenesulfonamide;
B-81 90 4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1- -yl)
benzenesulfonamide; B-82 91
4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl) benzenesulfonamide;
B-83 92 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-- 1H-pyrazol-
1-yl)benzenesulfonamide; B-84 93
4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-
yl)benzenesulfonamide; B-85 94
4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-
1-yl)benzenesulfonamide; B-86 95
4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl) benzenesulfonamide; B-87
96 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-- pyrazol-1-
yl]benzenesulfonamide; B-88 97
4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]
benzenesulfonamide; B-89 98
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-
pyrazol-1-yl]benzenesulfonamide; B-90 99
4[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-
1-yl]benzenesulfonamide; B-91 100
4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide; B-92 101
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-
1-yl]benzenesulfonamide; B-93 102
4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-
pyrazol-1-yl]benzenesulfonamide; B-94 103
4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-
1-yl]benzenesulfonamide; B-95 104
4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide;
B-96 105 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-
pyrazol-1-yl]benzenesulfonamide; B-97 106
4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl] benzenesulfonamide;
B-98 107 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-
1H-pyrazol-1-yl]benzenesulfonamide; B-99 108
4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-
1H-pyrazol-1-yl]benzenesulfonamide; B-100 109
4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide; B-101 110
4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-
yl]benzenesulfonamide; B-102 111
4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-
1H-pyrazol-1-yl]benzenesulfonamide; B-103 112
5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]
spiro[2.4]hept-5-ene; B-104 113
4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5- yl]benzenesulfonamide;
B-105 114 6-(4-fluorophenyl)-7-[4-methylsulfonyl)phenyl]
spiro[3.4]oct-6-ene; B-106 115
5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)
phenyl]spiro[2.4]hept-5-ene; B-107 116
4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-
5-yl]benzenesulfonamide; B-108 117
5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)
phenyl]spiro[2.4]hept-5-ene; B-109 118
5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]
spiro[2.4]hept-5-ene; B-110 119
4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-
yl]benzenesulfonamide; B-111 120
2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-
methylsulfonylphenyl)thiazole; B-112 121
2-(2-chloropbenyl)-4-(4-fluorophenyl)-5-(4-
methylsulfonylphenyl)thiazole; B-113 122
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2- methylthiazole;
B-114 123 4-(4-fluorophenyl)-5-(4-methylsulfonylp- henyl)-2-
trifluoromethylthiazole; B-115 124
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-
(2-thienyl)thiazole; B-116 125
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-
benzylaminothiazole; B-117 126
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-
(1-propylamino)thiazole; B-118 127
2-((3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-
5-[4-(methylsulfonyl)phenyl]thiazole; B-119 128
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-
trifluoromethylthiazole; B-120 129
1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)
cyclopenta-2,4-dien-3-yl]benzene; B-121 130
4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-
dien-3-yl]benzenesulfonamide; B-122 131
5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]
spiro[2.4]hepta-4,6-diene; B-123 132
4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-
5-yl]benzenesulfonamide; B-124 133
6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)
phenyl]-pyridine-3-carbonitrile; B-125 134
2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
pyridine-3-carbonitrile; B-126 135
6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-
phenyl-pyridine-3-carbonitrile; B-127 136
4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-
imidazol-1-yl]benzenesulfonamide; B-128 137
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-
imidazol-1-yl]benzenesulfonamide; B-129 138
4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-
imidazol-1-yl]benzenesulfonamide; B-130 139
3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-
1H-imidazol-2-yl]pyridine; B-131 140
2-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)]-
1H-imidazol-2-yl]pyridine; B-132 141
2-methyl-4-[1-[4-(methylsulfonyl)phenyl-4-
(trifluoromethyl)]-1H-imidazol-2-yl]pyridine; B-133 142
2-methyl-6-[1-[4-(methylsulfonyl)phenyl-4-
(trifluoromethyl)]-1H-imidazol-2-yl]pyridine; B-134 143
4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-
1H-imidazol-1-yl]benzenesulfonamide; B-135 144
2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-
4-(trifluoromethyl)-1H-imidazole; B-136 145
4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1H-
imidazol-1-yl]benzenesulfonamide; B-137 146
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-
methyl-1H-imidazole; B-138 147
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-
phenyl-1H-imidazole; B-139 148
2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-
(methylsulfonyl)phenyl]-1H-imidazole; B-140 149
2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-
4-(trifluoromethyl)]-1H-imidazole; B-141 150
1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-
1H-imidazole; B-142 151 2-(4-methylphenyl)-1-[4-(-
methylsulfonyl)phenyl]-4- trifluoromethyl-1H-imidazole; B-143 152
4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)- -
1H-imidazol-1-yl]benzenesulfonamide; B-144 153
2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-
4-(trifluoromethyl)-1H-imidazole; B-145 154
4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl-
1H-imidazole-1-yl]benzenesulfonamide; B-146 155
2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-
trifluoromethyl-1H-imidazole; B-147 156
4-[2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazoi-1-
yl]benzenesulfonamide; B-148 157
1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-
4-trifluoromethyl-1H-imidazole B-149 158
4-[2-(3-chlorophenyl)-4-trifluoromethyl-1H-
imidazol-1-yl]benzenesulfonamide; B-150 159
4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1- yl]benzenesulfonamide;
B-151 160 4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-
1H-imidazol-1-yl]benzenesulfonamide; B-152 161
1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-
5-(trifluoromethyl)-1H-pyrazole; B-153 162
4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-
pyrazol-3-yl]benzenesulfonamide; B-154 163
N-phenyl-[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-
5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide; B-155 164
ethyl[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-
5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate; B-156 165
4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-
phenylethyl)-1H-pyrazole; B-157 166
4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-
1-(2-phenylethyl)-5-(trifluoromethyl)pyrazole; B-158 167
1-ethyl-4-(4-fluorophenyl)-3-[4-methylsulfonyl)phenyl]-
5-(trifluoromethyl)-1H-pyrazole; B-159 168
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-
2-trifluoromethyl-1H-imidazole; B-160 169
4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-
(trifluoromethyl)-1H-imidazole; B-161 170
5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)
phenyl]-6-(trifluoromethyl)pyridine; B-162 171
2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-
6-(trifluoromethyl)pyridine; B-163 172
5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-
(2-propynyloxy)-6-(trifluoromethyl)pyridine; B-164 173
2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-
6-(trifluoromethyl)pyridine; B-165 174
4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]
benzenesulfonamide; B-166 175
1-(4-fluorophenyl)-2-[4-methylsulfonyl)phenyl]benzene; B-167 176
5-difluoromethyl-4-(4-methylsulfonylphenyl)-3- phenylisoxazole;
B-168 177 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide;
B-169 178 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]
benzenesulfonamide; B-170 179
4-[5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide; B-171
180 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenes- ulfonamide; B-172
181 1-[2-(4-fluorophenyl)cyclope- nten-1-yl]-4-
(methylsulfonyl)benzene; B-173 182
1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene; B-174 183
1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4- (methylsulfonyl)benzene-
; B-175 184 1-[2-(2,4-dichlorophenyl)cyclopenten-1- -yl]-4-
(methylsulfonyl)benzene; B-176 185
1-[2-(4-trifloromethylphenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene; B-177 186
1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene; B-178 187
1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-
yl]-4-(methylsulfonyl)benzene; B-179 188
4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-
yl]benzenesulfonamide; B-180 189
1-[2-(3-chlorophenyl)-4,4-dimethylcyclopenten-1-
yl]-4-(methylsulfonyl)benzene; B-181 190
4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-
yl]benzenesulfonamide; B-182 191
4-[2-(4-fluorophenyl)cyclopenten-1- yl]benzenesulfonamide, B-183
192 4-[2-(4-chlorophenyl)cyclopenten-1- yl]benzenesulfonamide;
B-184 193 1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene; B-185 194
1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene; B-186 195
4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-
yl]benzenesulfonamide; B-187 196
1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene; B-188 197
4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1- yl]benzenesulfonamide;
B-189 198 4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]
benzenesulfonamide; B-190 199 ethyl
2-[4-(4-fluorophenyl)-5-[4-(methy- lsulfonyl)
phenyl]oxazol-2-yl]-2-benzyl-acetate; B-191 200
2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)
phenyl]oxazol-2-yl]acetic acid; B-192 201
2-(tert-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)
phenyl]oxazole; B-193 202 4-(4-fluorophenyl)-5-[4-
-(methylsulfonyl)phenyl9 -2- phenyloxazole; B-194 203
4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl) phenyl]oxazole;
B-195 204 4-[5-(3-fluoro-4-methox- yphenyl)-2-trifluoromethyl-
4-oxazolyl]benzenesulfonamide; B-196 205
6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethy- l-2H-
1-benzopyran-3-carboxylic acid; B-197 206
6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic
acid; B-198 207 5,5-dimethyl-3-(3-fluorophenyl)-4-methyl
sulfonyl-2(5H)- furanone; B-199 208 6-chloro-2-trifluoromethyl-2N-
-1-benzothiopyran-3- carboxylic acid; B-200 209
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-
1-yl]benzenesulfonamide; B-201 210
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-
1-yl]benzenesulfonamide; B-202 211
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-
1H-pyrazol-1-yl]benzenesulfonamide; B-203 212
3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-
1H-imidazol-2-yl]pyridine; B-204 213
2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-
trifluoromethyl-1H-imidazol-2-yl]pyridine; B-205 214
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-
1H-imidazoI-1-yl]benzenesulfonamide; B-206 215
4-(5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide; B-207 216
4-[5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide; B-208
217 [2-trifluoromethyl-5-(3,4-difluorophenyl)-4-
oxazolyl]benzenesulfonamide; B-209 218
4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; B-210 219
4-[5-(2-fluoro-4-methoxyphenyl)-2-trifluoromethyl-
4-oxazolyl]benzenesulfonamide; B-211 220 B-212 221
N-(4-nitro-2-phenoxy-phenyl)-methanesulfonamide or Nimesulide B-213
222 N-[6-(2,4-difluoro-phenox- y)-1-oxo-inden-5-yl]-
methanesulfonamide or Flosulide B-214 223
N-[6-(2,4-difluoro-phenylsulfanyl)-1-oxo-1H-inden-
5-yl]-methanesulfonamide, soldium salt, or L-745337 B-215 224
N-[5-(4-fluoro-phenylsulfanyl)-thiophen-2-yl]- methanesulfonamide
or RWJ-63556 B-216 225
3-(3,4-difluoro-phenoxy)-4-(4-methanesulfonyl-phenyl)-5-
methyl-5-(2,2,2-trifluoro-ethyl)-5H-furan-2-one or L-784512 B-217
226 (5Z)-2-amino-5-[[3,5-bis(1,1-dimethylethyl)-4- -
hydroxyphenyl]methylene]-4(5H)-thiazolone or Darbufelone B-218
CS-502 B-219 LAS-34475 B-220 LAS-34555 B-221 S-33516 B-222 SD-8381
B-223 L-783003 B-224 227 N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-
-benzopyran- 7-yl]-methanesulfonamide or T614 B-225 D-1367 B-226
L-748731 B-227 228
(6aR,10aR)-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-
1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9- carboxylic acid or
CT3 B-228 CGP-28238 B-229 229
4-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]
methylene]dihydro-2-methyl-2H-1,2-oxazin-3(4H)- one or BF-389 B-230
GR-253035 B-231 230 2-(6-dioxo-9H-purin-8-yl)cinnamic acid B-232
S-2474 B-233 231
[0413] The cyclooxygenase-2 selective inhibitors utilized in the
present invention may be in the form of free bases or
pharmaceutically acceptable acid addition salts thereof. The term
"pharmaceutically-acceptable salts" embraces salts commonly used to
form alkali metal salts and to form addition salts of free acids or
free bases. The nature of the salt may vary, provided that it is
pharmaceutically-acceptable. Suitable pharmaceutically-acceptable
acid addition salts of compounds for use in the present methods may
be prepared from an inorganic acid or from an organic acid.
Examples of such inorganic acids are hydrochloric, hydrobromic,
hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and
sulfonic classes of organic acids, examples of which are formic,
acetic, propionic, succinic, glycolic, gluconic, lactic, malic,
tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,
aspartic, glutamic, benzoic, anthranilic, mesylic,
4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,
cyclohexylaminosulfonic, stearic, algenic, .beta.-hydroxybutyric,
salicylic, galactaric and galacturonic acid. Suitable
pharmaceutically-acceptable base addition salts of compounds of use
in the present methods include metallic salts made from aluminum,
calcium, lithium, magnesium, potassium, sodium and zinc or organic
salts made from N,N'-dibenzylethylenediamine, chloroprocaine,
choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procaine. All of these salts may be
prepared by conventional means from the corresponding compound by
reacting, for example, the appropriate acid or base with the
compound of any Formula set forth herein.
[0414] The cyclooxygenase-2 selective inhibitors useful in the
practice of the present invention can be formulated into
pharmaceutical compositions and administered by any means that will
deliver a therapeutically effective dose. Such compositions can be
administered orally, parenterally, by inhalation spray, rectally,
intradermally, transdermally, or topically in dosage unit
formulations containing conventional nontoxic pharmaceutically
acceptable carriers, adjuvants, and vehicles as desired. Topical
administration may also involve the use of transdermal
administration such as transdermal patches or iontophoresis
devices. The term parenteral as used herein includes subcutaneous,
intravenous, intramuscular, or intrasternal injection, or infusion
techniques. Formulation of drugs is discussed in, for example,
Hoover, John E., Remington's Pharmaceutical Sciences, Mack
Publishing Co., Easton, Pa. (1975), and Liberman, H. A. and
Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New
York, N.Y. (1980).
[0415] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions, can be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic
parenterally acceptable diluent or solvent. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution, and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose, any bland fixed oil may be
employed, including synthetic mono- or diglycerides. In addition,
fatty acids such as oleic acid are useful in the preparation of
injectables. Dimethyl acetamide, surfactants including ionic and
non-ionic detergents, and polyethylene glycols can be used.
Mixtures of solvents and wetting agents such as those discussed
above are also useful.
[0416] Suppositories for rectal administration of the compounds
discussed herein can be prepared by mixing the active agent with a
suitable non-irritating excipient such as cocoa butter, synthetic
mono-, di-, or triglycerides, fatty acids, or polyethylene glycols
which are solid at ordinary temperatures but liquid at the rectal
temperature, and which will therefore melt in the rectum and
release the drug.
[0417] Solid dosage forms for oral administration may include
capsules, tablets, pills, powders, and granules. In such solid
dosage forms, the compounds are ordinarily combined with one or
more adjuvants appropriate to the indicated route of
administration. If administered per os, the compounds can be
admixed with lactose, sucrose, starch powder, cellulose esters of
alkanoic acids, cellulose alkyl esters, talc, stearic acid,
magnesium stearate, magnesium oxide, sodium and calcium salts of
phosphoric and sulfuric acids, gelatin, acacia gum, sodium
alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then
tableted or encapsulated for convenient administration. Such
capsules or tablets can contain a controlled-release formulation as
can be provided in a dispersion of active compound in
hydroxypropylmethyl cellulose. In the case of capsules, tablets,
and pills, the dosage forms can also comprise buffering agents such
as sodium citrate, or magnesium or calcium carbonate or
bicarbonate. Tablets and pills can additionally be prepared with
enteric coatings.
[0418] For therapeutic purposes, formulations for parenteral
administration can be in the form of aqueous or non-aqueous
isotonic sterile injection solutions or suspensions. These
solutions and suspensions can be prepared from sterile powders or
granules having one or more of the carriers or diluents mentioned
for use in the formulations for oral administration. The compounds
can be dissolved in water, polyethylene glycol, propylene glycol,
ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl
alcohol, sodium chloride, and/or various buffers. Other adjuvants
and modes of administration are well and widely known in the
pharmaceutical art.
[0419] Liquid dosage forms for oral administration can include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing inert diluents commonly used in the
art, such as water. Such compositions can also comprise adjuvants,
such as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring, and perfuming agents.
[0420] The amount of active ingredient that can be combined with
the carrier materials to produce a single dosage of the
cyclooxygenase-2 selective inhibitor will vary depending upon the
patient and the particular mode of administration. In general, the
pharmaceutical compositions may contain a cyclooxygenase-2
selective inhibitor in the range of about 0.1 to 2000 mg,
preferably in the range of about 0.5 to 500 mg and most preferably
between about 1 and 200 mg. A daily dose of about 0.01 to 100 mg/kg
body weight, preferably between about 0.1 and about 50 mg/kg body
weight and most preferably from about 1 to 20 mg/kg body weight,
may be appropriate. The daily dose can be administered in one to
four doses per day.
[0421] In one embodiment, when the cyclooxygenase-2 selective
inhibitor comprises rofecoxib, it is preferred that the amount used
is within a range of from about 0.15 to about 1.0
mg/day.multidot.kg, and even more preferably from about 0.18 to
about 0.4 mg/day.multidot.kg.
[0422] In still another embodiment, when the cyclooxygenase-2
selective inhibitor comprises etoricoxib, it is preferred that the
amount used is within a range of from about 0.5 to about 5
mg/day.multidot.kg, and even more preferably from about 0.8 to
about 4 mg/day.multidot.kg.
[0423] Further, when the cyclooxygenase-2 selective inhibitor
comprises celecoxib, it is preferred that the amount used is within
a range of from about 1 to about 20 mg/day.multidot.kg, even more
preferably from about 1.4 to about 8.6 mg/day.multidot.kg, and yet
more preferably from about 2 to about 3 mg/day.multidot.kg.
[0424] When the cyclooxygenase-2 selective inhibitor comprises
valdecoxib, it is preferred that the amount used is within a range
of from about 0.1 to about 5 mg/day.multidot.kg, and even more
preferably from about 0.8 to about 4 mg/day.multidot.kg.
[0425] In a further embodiment, when the cyclooxygenase-2 selective
inhibitor comprises parecoxib, it is preferred that the amount used
is within a range of from about 0.1 to about 5 mg/day.multidot.kg,
and even more preferably from about 1 to about 3
mg/day.multidot.kg.
[0426] Those skilled in the art will appreciate that dosages may
also be determined with guidance from Goodman & Goldman's The
Pharmacological Basis of Therapeutics, Ninth Edition (1996),
Appendix II, pp. 1707-1711 and from Goodman & Goldman's The
Pharmacological Basis of Therapeutics, Tenth Edition (2001),
Appendix II, pp. 475-493.
[0427] Amyloid Beta Vaccines
[0428] In addition to a cyclooxygenase-2 selective inhibitor, the
combination therapy of the present invention also comprises an
amyloid beta vaccine, wherein the vaccine comprises at least one
Abeta peptide that is generally deposited in amyloid plaques, or a
fragment, analog or variant thereof. While not being bound to a
particular theory, the amyloid beta vaccines of the present
invention appear to exhibit therapeutic effects due to their
immunogenicity and resulting production of antibodies. These
antibodies are believed to bind to soluble amyloid peptides and
neutralize them before they deposit into amyliod plaques and/or
bind to already-formed plaques and assist in their removal.
[0429] For preparation of amyloid beta vaccines, different isoforms
of the amyloid beta peptide are used. Furthermore, the vaccine can
comprise fragments, variants, or analogs of Abeta. The amyloid
peptides that can be used in vaccine preparation include but are
not limited to: Abeta (1-42), Abeta (1-43), Abeta (1-40), Abeta
(1-39), and Abeta (1-41). Furthermore, the fragments of Abeta that
can be used include but are not limited to: Abeta (1-28), Abeta
(1-16), Abeta (25-35), Abeta (29-39), Abeta (29-40), Abeta (29-41),
Abeta (29-42), Abeta (29-43), Abeta (26-42), Abeta (26-43), and
Abeta (35-43). In a preferred embodiment, the amyloid beta peptide
used to prepare an amyloid vaccine of the present invention
comprises Abeta (1-42).
[0430] For the purposes of the present invention, the vaccine can
be either monovalent (consisting of only one antigen) or
multivalent (containing more than one antigen), wherein the antigen
refers to Abeta peptide or a fragment, variant or analog thereof.
Accordingly, the monovalent vaccine of the present invention
comprises one Abeta peptide or one Abeta fragment, variant or
analog thereof whereas the multivalent vaccine comprises at least
two isoforms of Abeta peptides, or at least two Abeta fragments,
variants or analogs, or a combination thereof. By way of example,
the monovalent vaccine comprises Abeta peptide (1-42) or Abeta
fragment (25-35), whereas the multivalent vaccine comprises, e.g.,
1) Abeta (1-42) and Abeta (1-40), or 2) Abeta (1-42) and Abeta
(25-35), or 3) Abeta (25-35) and Abeta (1-28).
[0431] In an alternative embodiment, the vaccines of the present
invention may be prepared from the amyloid beta peptide nucleic
acid sequences and/or suitable vectors containing said nucleotide
sequences. Similarly to peptide vaccines, it is believed that the
nucleic acid vaccines elicit an immune response in a subject,
wherein the response includes production of anti-amyloid beta
antibodies.
[0432] Peptide Synthesis
[0433] Skilled artisans will recognize that the amyloid beta
peptides of the present invention and fragments, variant and
analogs thereof can be synthesized by a number of different
methods. All of the amino acid compounds of the invention can be
made by chemical methods well known in the art, including, e.g.,
solid phase peptide synthesis and recombinant methods. Both methods
are described, for instance, in U.S. Pat. No. 4,617,149.
[0434] Furthermore, the principles of solid phase chemical
synthesis of polypeptides are well known in the art and may be
found in general texts in the area. See, e.g., H. Dugas and C.
Penney, BIOORGANIC CHEMISTRY, (1981) Springer-Verlag, New York,
pgs. 54-92. For example, peptides may be synthesized by solid-phase
methodology utilizing an Applied Biosystems 430A peptide
synthesizer (commercially available from Applied Biosystems, Foster
City Calif.) and synthesis cycles supplied by Applied Biosystems.
Protected amino acids, such as t-butoxycarbonyl-protected amino
acids, and other reagents are commercially available from many
chemical supply houses. By way of example, Fraser et al. manuscript
describes the procedure for synthesizing Abeta peptides and
fragments thereof using FMOC solid phase procedure (J Neurosci Res,
28(4):474-485, 1991).
[0435] Recombinant Peptides
[0436] In addition, the DNA sequences encoding the amyloid beta
peptides or fragments, analogs or variants thereof can be produced.
The synthesis of nucleic acids is well known in the art. See, e.g.,
E. L. Brown, R. Belagaje, M. J. Ryan, and H. G. Khorana, Methods in
Enzymology, 68:109-151 (1979). The DNA segments corresponding to
the amyloid beta peptides or fragments thereof can be generated
using conventional DNA synthesizing apparatus such as the Applied
Biosystems Model 380A or 380B DNA synthesizers (commercially
available from Applied Biosystems, Inc., 850 Lincoln Center Drive,
Foster City, Calif. 94404) which employ phosphoramidite chemistry.
In the alternative, the more traditional phosphotriester chemistry
may be employed to synthesize the nucleic acids of this invention.
See, e.g., OLIGONUCLEOTIDE SYNTHESIS, A PRACTICAL APPROACH, (M. J.
Gait, ed., 1984).
[0437] Following the synthesis of DNA sequences, such sequences are
produced by utilizing recombinant systems. The basic steps in the
recombinant production of desired peptides are: integrating said
DNA into an expression vector in a manner suitable for the
expression of the peptide of interest, either alone or as a fusion
protein; transforming an appropriate eukaryotic or prokaryotic host
cell with said expression vector; culturing said transformed or
transfected host cell in a manner to express the peptide of
interest; and recovering and purifying the recombinantly produced
peptide of interest.
[0438] The methods of recombinantly producing peptides/proteins are
well known in the art. Literature that describes these techniques
includes, for example, Sambrook, et al., Molecular Cloning: A
Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring
Harbor, N.Y. (2nd edition, 1989); Ausubel, et al., Current
Protocols in Molecular Biology (1987); O'Reilly, et al.,
Baculovirus Expression Vectors: A Laboratory Manual (1992);
Practical Molecular Virology (Collins, ed., 1991); Culture of
Animal Cells: A Manual of Basic Technique (Freshney, ed., 2nd
edition, 1989); J. Miller, Experiments in Molecular Genetics, Cold
Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1972); D. A.
Morrison, Transformation and Preservation of Competent Bacterial
Cells by Freezing, Methods Enzymol. 68:326-331 (1979); and J.
Perbal, A Practical Guide to Molecular Cloning, John Wiley &
Sons (1984).
[0439] Peptide Purification
[0440] After the desired peptide is obtained either by chemical
synthesis or recombinant methods, it can be isolated and purified
using a number of procedures that are well known in the art, such
as, e.g., extraction, precipitation, chromatography, affinity
chromatography, electrophoresis, or the like. For example,
purification of amyloid beta peptides following FMOC synthesis by
high pressure liquid chromatography (HPLC) is described in Fraser
et al. (J Neurosci Res, 28(4):474-485, 1991).
[0441] Preparation and Administration of Vaccines
[0442] Immunogenic vaccines of the present invention may be
administered parenterally, such as by injection subcutaneously,
intramuscularly, intradermally, intraperitoneally, or
intravenously. Alternatively, other modes of administration
including suppositories and oral formulations may be desirable. The
one or more amyloid beta peptides and/or fragments, analogs or
variants thereof may be mixed with pharmaceutically acceptable
excipients or carriers, which are compatible therewith. Such
excipients may include, water, saline, dextrose, glycerol, ethanol,
and combinations thereof. For suppositories, binders and carriers
may include, for example, polyalkalene glycols or triglycerides.
Oral formulations may include normally employed incipients such as,
for example, pharmaceutical grades of saccharine, cellulose and
magnesium carbonate. These compositions can take the form of
solutions, suspensions, tablets, pills, capsules, sustained release
formulations or powders and contain about 1 to 95% of the amyloid
beta peptide or fragment, analog, or variant thereof.
[0443] The immunogenic vaccines may further contain auxiliary
substances, such as wetting or emulsifying agents, pH buffering
agents, or adjuvants to enhance the effectiveness thereof. Vaccine
preparation is generally described in New Trends and Developments
in Vaccines, edited by Voller et al., University Park Press,
Baltimore, Md., U.S.A. 1978 and Remington's Pharmaceutical Science;
Mack Publishing Company Easton, Pa. (latest edition).
[0444] Immunogenicity can be significantly improved if the antigens
are co-administered with adjuvants, commonly used as 0.05 to 0.1
percent solutions in phosphate-buffered saline. Adjuvants enhance
the immunogenicity of an antigen but are not necessarily
immunogenic themselves. Adjuvants may act by retaining the antigen
locally near the site of administration to produce a depot effect
facilitating a slow, sustained release of antigen to cells of the
immune system. Adjuvants can also attract cells of the immune
system to an antigen depot and stimulate such cells to elicit
immune responses. Intrinsic adjuvants, such as lipopolysaccharides,
are generally the components of the killed or attenuated bacteria
used as vaccines. Extrinsic adjuvants are immunomodulators which
are typically non-covalently linked to antigens and are formulated
to enhance the host immune responses.
[0445] Desirable characteristics of ideal adjuvants include: lack
of toxicity; ability to stimulate a long-lasting immune response;
simplicity of manufacture and stability in long-term storage;
ability to elicit the desirable response to antigens administered
by various routes, (e.g. for the treatment of Alzheimer's disease,
production of antibodies that are able to bind to and
neutralize/clear amyloid beta peptides is desirable); synergy with
other adjuvants; capability of selectively interacting with
populations of antigen presenting cells (APC); and the ability to
selectively increase appropriate antibody isotype levels (for
example, IgG) against antigens.
[0446] Accordingly, the vaccines of the present invention may be
formulated with various adjuvants or immunomodulating agents
including, for example, aluminum hydroxide, aluminum phosphate,
aluminum potassium sulfate (alum), beryllium sulfate, silica,
kaolin, carbon, water-in-oil emulsions, oil-in-water emulsions,
muramyl dipeptide, bacterial endotoxin, lipid X, Corynebacterium
parvum (Propionibacterium acnes), Bordetella pertussis,
polyribonucleotides, sodium alginate, lanolin, lysolecithin,
vitamin A, saponin, liposomes, levamisole, DEAE-dextran, blocked
copolymers or other synthetic adjuvants. Such adjuvants are
available commercially from various sources, for example, Merck
Adjuvant 65 (Merck and Company, Inc., Rahway, N.J.). Adjuvants,
including liposomes, are discussed in the following references,
e.g., :Gregoriades, G. et al., Immunological Adjuvants and
Vaccines, Plenum Press, New York, 1989 Michalek, S. M. et al.,
"Liposomes as Oral Adjuvants," Curr. Top. Microbiol. Immunol.
146:51-58 (1989).
[0447] Aluminum hydroxide and aluminum phosphate (collectively
commonly referred to as alum) are routinely used as adjuvants in
human and veterinary vaccines. For example, the efficacy of alum in
increasing antibody responses to diphtheria and tetanus toxoids is
well established. Thus, in a preferred embodiment, the adjuvant
used to produce amyloid beta vaccines of the present invention
comprises aluminum hydroxide or aluminum phosphate.
[0448] In another embodiment, oil in water emulsions per se are
well known in the art, and have been suggested to be useful as
adjuvant compositions (see, e.g., EPO 399843). In order for any oil
in water composition to be suitable for human administration, the
oil phase of the emulsion system has to comprise a metabolizable
oil, that is, an oil "capable of being transformed by metabolism"
(Dorland's Illustrated Medical Dictionary, W. B. Sanders Company,
25th edition (1974)). The oil may be any vegetable oil, fish oil,
animal oil or synthetic oil, which is not toxic to the recipient
and is capable of being transformed by metabolism. Nuts, seeds, and
grains are common sources of vegetable oils. Synthetic oils are
also part of this invention and can include commercially available
oils.
[0449] For formulation of amyloid beta nucleic acid vaccines, the
vaccines may be prepared as injectables, in
physiologically-acceptable liquid solutions or emulsions for
polynucleotide administration. The nucleic acid may be associated
with liposomes, such as lecithin liposomes or other liposomes known
in the art or the nucleic acid may be associated with an adjuvant,
as previously described. Liposomes comprising cationic lipids
interact spontaneously and rapidly with polyanions, such as DNA and
RNA, resulting in liposome/nucleic acid complexes that capture up
to 100% of the polynucleotide. In addition, the polycationic
complexes fuse with cell membranes, resulting in an intracellular
delivery of polynucleotide that bypasses the degradative enzymes of
the lysosomal compartment. PCT application WO 94/27435 describes
compositions for genetic immunization comprising cationic lipids
and polynucleotides. Furthermore, in order to assist the cellular
uptake of nucleic acid, agents, such as calcium ions, viral
proteins and other transfection facilitating agents, may be
advantageously used.
[0450] The immunogenic vaccines of the present invention are
administered in a manner compatible with the dosage formulation,
and in such amount as will be therapeutically effective, protective
and immunogenic. The quantity to be administered depends on the
subject to be treated, including, for example, the capacity of the
individual's immune system to synthesize antibodies, and if needed,
to produce a cell-mediated immune response. Precise amounts of
active ingredient required to be administered depend on the
judgment of the practitioner. However, suitable dosage ranges are
readily determinable by one skilled in the art and may be of the
order of micrograms of the amyloid beta peptides or fragments
thereof. Suitable regimes for initial administration and booster
doses are also variable, but may include an initial administration
followed by subsequent administrations. The dosage may also depend
on the route of administration and will vary according to the size
of the host.
[0451] Generally, it is expected that each dose will comprise the
amyloid beta peptide(s) in the amount between about 0.01 .mu.g/kg
body weight and about 1000 .mu.g/kg body weight of the subject.
Preferably, each dose will be about 500 .mu.g/kg body weight of the
peptide(s), and more preferably about 300 .mu.g/kg body weight of
the amyloid beta peptide(s). An optimal amount for a particular
vaccine can be ascertained by standard studies involving
observation of appropriate immune responses in subjects. Following
an initial vaccination, subjects may receive one or several booster
immunizations adequately spaced, for example after 2 and 6 months.
In another embodiment, an amyloid beta vaccine may be administered
to a subject at regularly spaced intervals, for example once/6
months. In addition, the vaccine may be administerd to a subject at
regularly spaced intervals for the life of the subject.
[0452] With respect to the Cox-2 inhibitor administration, the
initial amyloid beta vaccine may be administered prior to the start
of a Cox-2 inhibitor administration. Other options include
administering a Cox-2 inhibitor prior to the initial amyloid
vaccination or administering it during the time intervals between
each vaccination.
[0453] Other embodiments within the scope of the embodiments herein
will be apparent to one skilled in the art from consideration of
the specification or practice of the invention as disclosed herein.
It is intended that the specification be considered to be exemplary
only, with the scope and spirit of the invention being indicated by
the embodiments.
[0454] All references cited in this specification, including
without limitation, all papers, publications, patents, patent
applications, presentations, texts, reports, manuscripts,
brochures, books, internet postings, journal articles, periodicals,
and the like, are hereby incorporated by reference into this
specification in their entireties.
[0455] As various changes could be made in the above methods and
compositions without departing from the scope of the invention, it
is intended that all matter contained in this application shall be
interpreted as illustrative and not in a limiting sense.
EXAMPLES
[0456] The following examples are intended to provide illustrations
of the application of the present invention. The following examples
are not intended to completely define or otherwise limit the scope
of the invention.
Example 1
Mouse Model of Alzheimer's Disease
[0457] PDAPP mice, transgenic for an amyloid .beta. precursor
protein (APP) mini-gene driven by a platelet-derived (PD) growth
factor promoter, overexpress one of the disease-linked mutant forms
of the human APP protein, and as a result exhibit many of the
pathological features of Alzheimer's disease including deposition
of extracellular amyloid plaques (Games et al., Nature, 373,
pp.523-527, 1995). Accordingly, these mice provide a suitable model
system for determining the effect of different treatments on
Alzheimer's disease.
[0458] Non-transgenic mice (healthy control mice), non-transgenic
mice receiving a placebo treatment, PDAPP mice receiving no
treatment, and PDAPP mice receiving a combination of Cox-2
inhibitor and amyloid immunizations are used to assess the efficacy
of the treatment. Non-transgenic mice are preferably of the same
genetic background as PDAPP mice.
[0459] For the experiment, combinations of different Cox-2
inhibitors and different amyloid beta vaccines are tested. For
example and without limitation, celecoxib is tested in combination
with Abeta (1-42)-comprising vaccine or in combination with Abeta
(1-28) vaccine, and rofecoxib is tested with either of the two
vaccines. However, it should be noted that any Cox-2 inhibitor
described herein could be tested in combination with any of the
amyloid beta vaccines described herein. Furthermore, for each
combination of a Cox-2 inhibitor and amyloid beta vaccine, several
different doses of Cox-2 inhibitor should be tested with several
doses of amyloid beta peptides contained in the vaccines to test
the efficacy of the treatment.
[0460] The results of the treatment can be determined through a
number of different tests. For example, a behavioral test, such as
a radial-arm maze or water maze, can be used to compare the
abilities of treated mice versus control mice. Specifically,
deleterious behavior, such as confusion and failure of memory, can
be evaluated based upon observation of the performance of mice in
such tests.
[0461] Additionally, numerous epidemiological tests can be
performed to determine the amount of swelling in the brain tissue,
the amount of amyloid plaque deposit and neurofibrillary tangle
deposit in the brain, and the amount of bound A.beta. found in the
plasma and cerebrospinal fluid. The methods for measuring the
above-mentioned characteristics are well known in the art. See, for
instance, Bard et al., Nature Medicine, Vol. 6, no. 8, pp.916-919,
August 2000 and Morgan et al., Nature, Vol. 408, pp. 982-985, 21/28
December 2000).
* * * * *